AU2011284688B2 - Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use - Google Patents

Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use Download PDF

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AU2011284688B2
AU2011284688B2 AU2011284688A AU2011284688A AU2011284688B2 AU 2011284688 B2 AU2011284688 B2 AU 2011284688B2 AU 2011284688 A AU2011284688 A AU 2011284688A AU 2011284688 A AU2011284688 A AU 2011284688A AU 2011284688 B2 AU2011284688 B2 AU 2011284688B2
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trans
compound
phenyl
cyclopropyl
methyl
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AU2011284688A1 (en
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Maria De Los Angeles Estiarte-Martinez
Matthew Colin Thor Fyfe
Marc Martinell Pedemonte
Alberto Ortega Munoz
Inigo Tirapu Fernandez De La Cuesta
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Oryzon Genomics SA
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including,

Description

WO 2012/013728 PCT/EP2011/062949 5 ARYLCYCLOPROPYLAMINE BASED DEMETHYLASE INHIBITORS OF LSD1 AND THEIR MEDICAL USE The invention relates to (hetero)aryl cyclopropylamine compounds, particularly the compounds of formula (I), (Ia), (Tb), (II) or (III) as described and defined herein, and their 10 use in therapy, including e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. Aberrant gene expression in affected tissue as compared to normal tissue is a common characteristic of many human diseases. This is true for cancer and many neurological 15 diseases which are characterized by changes in gene expression patterns. Gene expression patterns are controlled at multiple levels in the cell. Control of gene expression can occur through modifications of DNA: DNA promoter methylation is associated with suppression of gene expression. Several inhibitors of DNA methylation are approved for clinical use including the blockbuster VidazaTM. Another class of modifications involve histones which 20 form the protein scaffold that DNA is normally associated with (coiled around) in eukaryotic cells. Histones play a crucial role in organizing DNA and the regulated coiling and uncoiling of DNA around the histones is critical in controlling gene expression - coiled DNA is typically not accessible for gene transcription. A number of histone modification have been discovered including histone acetylation, histone lysine methylation, histone 25 arginine methylation, histone ubiquinylation, and histone sumoylation, many of which modify accessibility to the associated DNA by the cells transcriptional machinery. These histone marks serve to recruit various protein complexes involved in transcription and repression. An increasing number of studies are painting an intricate picture of how various combinations of histone marks control gene expression in cell-type specific manner and a 30 new term has been coined to capture this concept: the histone code. The prototypical histone mark is histone acetylation. Histone acetyl transferase and histone deacetylases are the catalytic machines involved in modulation of this histone mark although typically these enzymes are parts of multiprotein complexes containing other WO 2012/013728 PCT/EP2011/062949 2 proteins involved in reading and modifying histone marks. The components of these protein complexes are typically cell type and typically comprise transcriptional regulators, repressors, co-reppresors, receptors associated with gene expression modulation (e.g., estrogen or androgen receptor). Histone deacetylase inhibitors alter the histone acetylation 5 profile of chromatin. Accordingly, histone deacetylase inhibitors like SAHA, TSA, and many others have been shown to alter gene expression in various in vitro and in vivo animal models. Clinically, histone deacetylase inhibitor have demonstrated activity in the cancer setting and are being investigated for oncology indications as well as for neurological conditions and other diseases. 10 Another modification that is involved in regulating gene expression is histone methylation including lysine and arginine methylation. The methylation status of histone lysines has recently been shown to be important in dynamically regulating gene expression. 15 A group of enzymes known as histone lysine methyl transferases and histone lysine demethylases are involved in histone lysine modifications. One particular human histone lysine demethylase enzyme called Lysine Specific Demethylase-1 (LSD1) was recently discovered (Shi et al. (2004) Cell 119:941) to be involved in this crucial histone modification. LSD1 has a fair degree of structural similarity, and amino acid 20 identity/homology to polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amine oxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/or nitrogen carbon bonds. Several groups have reported LSD1 inhibitors in the literature. Sharma et al. recently 25 reported a new series of urea and thiourea analogs based on an earlier series of polyamines which were shown to inhibit LSDl and modulate histone methylation and gene expression in cells ((2010) J. Med. Chem. PMID: 20568780). Sharma et al. note that "To date, only a few existing compounds have been shown to inhibit LSD1." Some efforts were made to make analogs of the histone peptide that is methylated by the enzyme, other efforts have 30 focused on more small molecule like molecules based on known MAO inhibitors. Cyclopropylamine containing compounds are known to inhibit a number of medically important targets including amine oxidases like Monoamine Oxidase A (MAO-A; or WO 2012/013728 PCT/EP2011/062949 3 MAOA), Monoamine Oxidase B (MAO-B; or MAOB), and Lysine Specific Demethylase-1 (LSD1). Tranylcypromine (also known as 2-phenylcyclopropylamine), which is the active ingredient of Parnate@ and one of the best known examples of a cyclopropylamine, is known to inhibit all of these enzymes. 5 Gooden et al. reported trans-2-arylcyclopropylamine analogues that inhibit LSD1 with Ki values is the range of 188-566 micromolar (Gooden et al. ((2008) Bioorg. Med. Chem. Let. 18:3047-3051)). Most of these compounds were more potent against MAO-A as compared to MAO-B. Ueda et al. ((2009) J. Am. Chem Soc. 131(48):17536-17537) reported cyclopropylamine analogs selective for LSD1 over MAO-A and MAO-B that were designed 10 based on reported X-ray crystal structures of these enzymes with a phenylcyclopropylamine-FAD adduct and a FAD-N-propargyl lysine peptide. The reported IC50 value for phenylcyclopropylamine was about 32 micromolar for LSD1 whereas compounds 1 and 2 had values of 2.5 and 1.9 micromolar respectively. 15 Mimasu et al. disclose a series of phenylcyclopropylamine derivatives having benzoyl substitutions at the ortho-position (2010) Biochemistry PMID: 20568732. Ortho-substituted compounds from this series without a benzoyl group in the ortho-position e.g., phenyl, alkoxy, or having a combination of ortho- and para- substitution appeared to be less potent inhibitors of LSD 1 than those compounds having benzoyl substituents in the ortho-position. 20 The most active compounds from this series had a benzoyl group at the ortho- position and one or two meta- fluoro substitutions: biphenyls like S1310 and compounds having large groups in the para- position were less effective LSD1 inhibitors. The phenylcyclopropylamines have been the subject of many studies designed to elucidate a 25 SAR for MAO inhibition. Kaiser et al. ((1962) J. Med. Chem. 5:1243-1265); Zirkle et al. ((1962) J. Med. Chem. 1265-1284; US patent nos. 3,365,458; 3,471,522; 3,532,749) have disclosed the synthesis and activity of a number of phenylcyclopropylamine related compounds. Other phenylcyclopropylamine type compounds are disclosed in Bolesov et al. ((1974) Zhurnal Organicheskoi Khimii 10:8 1661-1669) and Russian Patent No. 230169 30 (19681030). Studies have been conducted with phenylcyclopropylamine related compounds to determine selectivity for MAO-A versus MAO-B since MAO-A inhibitors can cause dangerous side- WO 2012/013728 PCT/EP2011/062949 4 effects (see e.g., Yoshida et al. (2004) Bioorg. Med Chem. 12(10):2645-2652; Hruschka et al. (2008) Biorg Med Chem. (16):7148-7166; Folks et al. (1983) J. Clin. Psychopharmacol. (3)249; and Youdim et al. (1983) Mod. Probl. Pharmacopsychiatry (19):63). 5 Binda et al. examined a series of phenylcyclopropylamine derivatives in relation to their inhibitory activity against LSD1 and LSD2 as well as examining stereochemical issues in relation to the cyclopropyl ring (J. Am. Chem. Soc. (2010) May 19;132(19):6827-33). Binda et al. reported that their para substituted phenylcyclopropylamine derivatives are non-selective which as a group are appear to be better MAO-A inhibitors than MAO-B 10 inhibitors. Furthermore, their inhibitory activities against MAO-A and LSD1 were roughly the same. Substituted cyclopropylamines can be chiral. Chiral compounds are often characterized by their ability to rotate plane polarized light and are typically referred to as (+) or (-) 15 depending on the direction they rotate the light. Another nomenclature is the d- and l which are short for dextrorotatory and levorotatory. R and S designation are used to specify absolute configurations since the ability of chiral molecules to rotate plane polarized light, e.g., the direction of rotation, does not correlate always with absolute configurations. 20 Tranylcypromine has two stereocenters corresponding to the carbons of the cyclopropyl ring that bear the amino substituent and the phenyl substituent. Theoretically, a compound having the phenylcyclopropylamine structure of tranylcypromine can have four stereochemical configurations: two corresponding to the cis (IS,2S or 1R,2R) and two corresponding to the trans (1S,2R or 1R,2S). Tranylcypromine corresponds to the trans 25 isomer of 2-phenylcyclopropylamine and is a racemate of the (-) and (+) enantiomers (i.e., a 50:50 mixture of the 1 S,2R and 1R,2S enantiomers) and, thus, is optically inactive. The (-) enantiomer of tranylcypromine was synthesized, characterized, and absolute configuration determined. Riley et al. (1972) J. Med. Chem. 15(11):1187-1188. The (-) 30 stereoisomer was determined to have the 1R,2S absolute configuration by synthesis from IR,2R-2-phenylcyclopropanecarboxylic acid. Later studies using other techniques confirmed this assignment (Binda et al. (2010) JACS 132:6827-6833) by determination of the X-ray structure of the para-bromo derivative of a stereoisomer of 2- WO 2012/013728 PCT/EP2011/062949 5 phenylcyclopropylamine and comparison to the CD spectra of the tranylcypromine stereoisomers. These results were confirmed by stereoselective synthesis of the enantiomers of tranylcypromine. 5 It is reported that the (+) isomer (1 S,2R) of trans-2-phenylcyclopropylamine is more potent against MAO than the (-) isomer (1R,2S) (Riley et al. (1972) J. Med. Chem. 15(11):1187 1188) using an in vivo tryptamine convulsion model (Zirkle et al. (1962) J. Med. Pharm. Chem. 5:1265). 10 Binda et al. reported a significant difference in the ability of the stereoisomers of tranylcypromine to inhibit MAO-B with the (+) stereoisomer being much more potent using in vitro biochemical assays. The (-) stereoisomer (1R,2S) was a slightly stronger inhibitor of LSD1 than the (+) stereoisomer (Ki of 168 uM versus a Ki of 284 uM) but these differences were considered marginal by the authors (Binda et al. ((2010) JACS 132:6827 15 6833 see page 6828). Recently, a group reported another investigation of the stereoisomers of tranylcypromine with LSD1 (Benelkebir et al. (2011) Bioorg Med. Chem.doi: 10.1016/j.bmc.2011.02.017). They found that the stereoisomers of tranylcypromine were about equipotent for LSD1: 20 Ki(inact) for the (+) stereoisomer was of 26.6 uM, 28.1 uM for the (-) stereoisomer and 25.0 uM for the racemate. Another group studying the effect of the stereochemical configuration around the cyclopropylamine group of substituted 2-phenylcyclopropylamine compounds reported the 25 stereoisomer having the (1 S,2R) absolute configuration (as determined by NMR using chiral shift reagents) was a more potent LSD 1 inhibitor as compared to its enantiomer, both in in vitro biochemical assays and cell based growth inhibition assays in Hela and HEK293, whereas the enantiomers behaved equally in the neuroblastoma line, SH-SY5Y (Ogasawara et al. (2011) Bioorg. Med. Chem. Doi:10.1016/j.bmc. 2010.12.024). 30 Given the differences in assays/experimental protocols used in the different studies referenced above, it is difficult to compare results between studies. Regardless, it is not clear from these data how derivatives or analogs of compounds having a WO 2012/013728 PCT/EP2011/062949 6 phenylcyclopropylamine core can be optimized to provide potent inhibitors of LSD 1, and LSDl and MAO-B, based on the stereochemical configuration of the carbons of the cyclopropyl moiety. Furthermore, it is not clear from these studies how the selectivity of N substituted aryl- and hetero- cyclopropylamine compounds for both LSD1 and MAO-B can 5 be modulated to provide compounds that inhibit these enzymes to a greater extent than MAO-A. Such compounds are expected to have beneficial safety windows by avoiding MAOA inhibition and the so-called "cheese effect". In view of the lack of adequate treatments for conditions such as cancer and 10 neurodegeneration, there is a desperate need for disease modifying drugs and drugs that work by inhibiting novel targets. There is a need for the development of better LSD1 selective inhibitors particularly those which selectively inhibit LSDl or LSD1 in combination with MAO-B. 15 SUMMARY OF THE INVENTION The present invention relates to the identification of compounds and their use in treating or preventing diseases. The invention provides (hetero)cyclopropylamine compounds, including the compounds of Formula (I), (II) or (III) as described and defined herein. The 20 present invention particularly provides a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, and their uses for treating diseases. One use of the compound of Formula (I) is for treating or preventing cancer. Another use for the compound of Formula (I) is to 25 inhibit LSD1. The present invention thus relates to a compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof for use in treating or preventing cancer. Thus, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further relates to its use in treating or preventing human disease. 30 Accordingly, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof: WO 2012/013728 PCT/EP2011/062949 7 (B)- (A) N H- (D) (I) (A) is a cyclyl group having n substituents (R3). 5 (B) is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclyl group or the cyclyl moiety comprised in said -(Ll)-cyclyl group has n substituents (R2). (LI) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene. 10 (D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein said heteroaryl group or the heteroaryl moiety comprised in said -(L2)-heteroaryl group has one substituent (RI), and further wherein said heteroaryl group is covalently bonded to the remainder of the molecule through a ring carbon atom or the heteroaryl moiety comprised in said -(L2)-heteroaryl 15 group is covalently bonded to the (L2) moiety through a ring carbon atom. (L2) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene. (RI) is a hydrogen bonding group. 20 Each (R2) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. 25 Each (R3) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. n is independently 0, 1, 2, 3 or 4. 30 WO 2012/013728 PCT/EP2011/062949 8 The substituents of the cyclopropyl moiety, i.e., the group (A) and the group -NH-CH 2 -(D), are preferably in the trans- configuration. In a related aspect, the invention provides a pharmaceutical composition comprising a 5 compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof as defined above and a pharmaceutically acceptable carrier. Preferred embodiments of the compound of Formula (I), e. g., for use in the composition of the invention are defined and described herein below in more detail. 10 In another aspect, the invention provides a method of treating or preventing a disease or condition comprising administering, to a patient (preferably a human) in need of treatment or prevention, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) as described above or as in the embodiments thereof as described below, or a pharmaceutically acceptable salt thereof and a pharmaceutically 15 acceptable carrier. This aspect can be reformulated as a compound of Formula (I) as defined above in the first aspect of the invention for use as a medicine. In a related aspect, the invention provides a pharmaceutical composition for use in treating or preventing a disease or condition wherein said composition comprises a therapeutically effective amount of a compound of Formula (I) sufficient for treating or preventing said disease or condition. 20 In a more specific embodiment, the invention provides a compound of Formula (I) for use in the treatment of a disease associated with LSD1. In yet another aspect, the invention provides a method of inhibiting LSD1 activity comprising administering, to a patient in need of treatment, a therapeutically effective 25 amount of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier sufficient to inhibit LSD1 activity. Preferably the patient is a human. This aspect can be reformulated as a compound of Formula (I) as herein defined for use as a LSD 1 inhibitor. In a related aspect, a method for treating an individual is provided, said method comprising identifying an individual in 30 need of treatment and administering to said individual a therapeutically effective amount of a compound of Formula (I). in a preferred aspect, the therapeutically effective amount of a compound of Formula (I) is an amount sufficient to inhibit LSD1. Preferred embodiments WO 2012/013728 PCT/EP2011/062949 9 of the compounds of Formula (I) for use in the composition and method of this aspect of the invention are as described in more detail herein. In again another aspect, the invention provides a method of treating or preventing cancer 5 comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of a composition comprising a compound of Formula (I) as defined above or as the embodiments described in more detail herein, and a pharmaceutically acceptable carrier. This aspect can be reformulated as a compound of Formula (I) as defined above in the first aspect of the invention for use in the treatment or prevention of cancer. In a related 10 aspect, the invention provides a pharmaceutical composition for use in treating or preventing cancer wherein said composition comprises a therapeutically effective amount of a compound of Formula (I) sufficient for treating or preventing cancer. In another related aspect, the invention provides a compound of Formula (I) or a pharmaceutical composition for the treatment or prevention of a cancer wherein said cancer is chosen from breast cancer, 15 lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma. Said composition preferably comprises a 20 therapeutically effective amount of a compound of Formula (I) sufficient for treating or preventing said cancer. In a preferred aspect, the therapeutically effective amount of a compound of Formula (I) is an amount sufficient to inhibit LSD1. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount is an 25 amount sufficient to modulate histone-3 lysine-4 methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. In again another aspect, the invention provides a method of treating or preventing a 30 neurological disease or condition comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of a composition comprising a compound of Formula (I) as defined above or in the embodiments described in more detail herein, and a pharmaceutically acceptable carrier. This aspect can be reformulated as a compound of WO 2012/013728 PCT/EP2011/062949 10 Formula (I) as defined above for use in the treatment or prevention of a neurological condition or disease. In a related aspect, the invention provides a pharmaceutical composition for use in treating or preventing a neurological condition or disease wherein said composition preferably comprises a therapeutically effective amount of a compound of 5 Formula (I) sufficient for treating or preventing said neurological disease or condition. In another related aspect, the invention provides a compound of Formula (I) or a pharmaceutical composition for the treatment or prevention of a neurological disease or condition wherein said neurological disease or condition is chosen from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic Lateral 10 Sclerosis, Dementia with Lewy Bodies, or Frontotemporal Dementia, particularly from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, or Dementia with Lewy Bodies. Said composition preferably comprises a therapeutically effective amount of a compound of Formula (I) sufficient for treating or preventing said disease or condition. In a preferred aspect, the therapeutically effective amount of a compound of Formula (I) is an 15 amount sufficient to inhibit LSD 1. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels. In 20 another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. In still another aspect, the invention provides a method for identifying a compound which is a selective inhibitor of LSD 1, the method comprising selecting or providing a compound of 25 Formula (I) as defined herein, and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSDl to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor. The compound of this aspect that is an LSDI inhibitor can be used to treat disease, particularly human disease. 30 In still another aspect, the invention provides a method for identifying a compound which is a dual inhibitor of LSDI and MAO-B, the method comprising selecting or providing a compound of Formula (I) as defined herein, and determining the ability of the compound to inhibit LSD 1, MAO-A, and MAO-B, wherein a compound that inhibits LSD 1 and MAO-B WO 2012/013728 PCT/EP2011/062949 11 to a greater extent than MAO-A is identified as a LSD1 MAO-B dual inhibitor. The compound of this aspect that is an LSDl MAO-B inhibitor can be used to treat disease, particularly human disease. 5 Thus, in one embodiment of the invention, the pharmaceutical composition comprising a LSDl selective inhibitor of Formula (I), or a pharmaceutically acceptable salt or solvate thereof is useful for treating and/or preventing a disease in an individual. In one aspect, a therapeutically effective amount of the composition is administered to an individual in an amount sufficient to prevent or treat a disease. In a more specific aspect, the disease is 10 cancer. In an even more specific aspect, the disease is a cancer chosen from prostate, brain, colorectal, lung, breast, skin, and blood cancer. In one specific aspect, the cancer is prostate cancer. In one specific aspect, the cancer is lung cancer. In one specific aspect, the cancer is brain cancer. In one specific aspect, the cancer is blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), 15 chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia). In one specific aspect, the cancer is breast cancer. In one specific aspect, the cancer is colorectal cancer. In one specific aspect, the cancer is lymphoma. In one specific aspect, the cancer is myeloma. In another preferred aspect, the therapeutically effective amount is an amount 20 sufficient to inhibit LSD 1. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-4 methylation levels. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. 25 Furthermore, the inventors unexpectedly found that the stereochemical configuration of the cyclopropyl carbons of N-substituted arylcyclopropylamine compounds substantially affects the potency of LSD1 inhibition, MAO-B inhibition and MAO-A inhibition. The inventors have shown that the (-) stereoisomer of 5-(((trans)-2-(4 30 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine is about 20-fold more potent against LSDI than the corresponding (+) stereoisomer. Furthermore, the (-) stereoisomer retained substantial MAO-B inhibitory activity. Notably, the selectivity for LSD 1/MAO-A for the (-)/(+) stereoisomer was over 100 fold as judged by kinact/K1 values.
WO 2012/013728 PCT/EP2011/062949 12 Thus, (-) stereoisomers of N-substituted (hetero)arylcyclopropylamine compounds are unexpectedly potent and selective LSD1 inhibitors compared to their respective enantiomers. Furthermore, the compounds of the invention have improved selectivity against MAO-A, preferentially inhibiting MAO-B and LSD1. The invention therefore 5 relates to optically active (hetero)arylcyclopropylamine compounds, in particular optically active N-substituted aryl- or heteroaryl- cyclopropylamines, and their use for treating or preventing a disease or a disorder. Thus, in one specific aspect the invention relates to a substantially pure stereoisomer of an 10 N-substituted aryl- or heteroaryl- cyclopropylamine (e.g., a compound of Formula (II) or (III) as described and defined herein below) for use in a method of treating or preventing a disease or disorder. Desirably, the disease or disorder is one that is treatable or preventable by LSD1 inhibition, LSD1 inhibition and MAO-B inhibition, or MAO-B inhibition. In a specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl 15 cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 90% or greater (-) stereoisomer and 10% or less (+) stereoisomer. In a more specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 95% or greater (-) stereoisomer and 5% or less (+) stereoisomer. In yet a more specific aspect, a substantially 20 pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N substituted aryl- or heteroaryl- cyclopropylamine which is 98% or greater (-) stereoisomer and 2% or less (+) stereoisomer. In an even more specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N substituted aryl- or heteroaryl- cyclopropylamine which is 99% or greater (-) stereoisomer 25 and 1% or less (+) stereoisomer. In yet an even more specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N substituted aryl- or heteroaryl- cyclopropylamine which is 99.5% or greater (-) stereoisomer and 0.5% or less (+) stereoisomer. In one embodiment, the above-described percentages refer to mole-%. The substantially pure stereoisomer of an N-substituted aryl- or heteroaryl 30 cyclopropylamine, in one aspect, is for use in a method of treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection.
WO 2012/013728 PCT/EP2011/062949 13 Furthermore, in another aspect, the invention is a composition comprising a stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine (e.g., a compound of Formula (II) or (III) as described and defined herein below) wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl 5 cyclopropylamine. In a specific aspect said composition has a 95% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. In a more specific aspect said composition has a 98% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. In an even more specific aspect said composition has a 99% or more enantiomeric excess of the (-) 10 stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. The composition in one aspect of the invention is for use in a method of treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection. Furthermore, in another aspect, the invention is a pharmaceutical composition comprising a 15 stereoisomer of an N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III) as described and defined herein below) and a pharmaceutically acceptable carrier wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. In a specific aspect said composition has a 95% or more enantiomeric excess of the (-) stereoisomer of 20 the N-substituted aryl- or heteroaryl- cyclopropylamine. In a specific aspect said composition has a 99% or more enantiomeric excess of the (-) stereoisomer of the N substituted aryl- or heteroaryl- cyclopropylamine. The pharmaceutical composition of this paragraph is for use in a method of treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection. 25 In one aspect of the invention, the optically active N-substituted aryl- or heteroaryl cyclopropylamine or pharmaceutically acceptable salt or solvate thereof, for use in a method of treating or preventing a disease or disorder, as described herein, is of Formula (II): 30 Ri 1 -(A")-R2r 1 (II) wherein: WO 2012/013728 PCT/EP2011/062949 14 (A") is an aryl or heteroaryl group having 2 substituents, RI" and R2", and 1, 2, or 3 optional substituents wherein said optional substituents are independently chosen from halo,
C
1
-C
3 alkyl, or C 1
-C
3 alkoxy; 5 R 1 " is an -(Li")-(R3") group; R3" is an aryl or heteroaryl group having 1, 2, 3, 4, or 5 optional substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 , wherein R is a C1-C 6 alkyl or phenyl; 10 L1" is chosen from a bond, -CH 2 0-, -CH 2
CH
2 0-, -OCH 2 -, - OCH 2
CH
2 -, - CH 2
CH
2 -, -CH 2 -,
-CH
2
CH
2
CH
2 -, or -0-; R2" is -Cyclopropyl-NH-(L 2 r')-(R4") wherein said cyclopropyl group has two chiral centers 15 substituted in the trans orientation corresponding to the carbons to which (A) and -NH
(L
2 r)-(R4") are covalently attached; R4" is a 5 or 6 membered heteroaryl ring having 1, 2, or 3 optional substituents chosen from alkyl, -NHR B, -OR B, or halo wherein RB is hydrogen ,C1-C 3 alkyl, or -C(=O)CH 3 ; 20
L
2 11 is a branched or unbranched C1-C 4 alkylene group and wherein said compound of Fomula (II) is optically active. 25 The invention also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl- cyclopropylamine of Formula (II) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 30 The invention also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (1) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or disorder. Preferably, the disease or WO 2012/013728 PCT/EP2011/062949 15 disorder is mediated through an amine oxidase. In one aspect, the amine oxidase is LSD1 or MAO-B. Furthermore, the inventors found a subset of optically active compounds of Formula (II) as 5 shown in Formula (III) which are inhibitors of LSD1 or of LSD1 and MAO-B. The invention thus further relates to an optically active compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof: 10 R1"'-(A"')-R2"1 (III) wherein: (A"') is an aryl or heteroaryl group having 2 substituents, R11" and R21", and 1, 2, or 3 15 optional substituents independently chosen from halo, Ci-C 3 alkyl, or C1-C 3 alkoxy; RI11 is an -(Lil")-(R31') group; R3"' is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2, 3, 4, or 5 optional 20 substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 , wherein RA is a C1-C 6 alkyl or phenyl; Li" is chosen from a bond, -OCH 2 -, or -CH 2 0-; 25 R21" is -Cyclopropyl-NH-(L 2 1 r)-(R4"') wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A 11 ) and -NH-(L211l)-(R4r1) are covalently attached; R4r1 is a 5-membered heteroaryl ring having 1, 2, or 3 optional substituents wherein said 30 optional substituents are independently chosen from -NH 2 or -NH(C1-C 3 ) alkyl; L2"' is -CH 2 - or -CH 2
CH
2
-;
WO 2012/013728 PCT/EP2011/062949 16 and wherein said compound of Formula (III) is optically active. Additionally, the invention is a pharmaceutical composition comprising an optically active N-substituted aryl- or heteroaryl- cyclopropylamine of Formula (II) or (III) as defined 5 above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The invention also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl- cyclopropylamine of Formula (II) or (III) as defined above, 10 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or disorder. In one aspect, the invention is a method of treating or preventing a disease or disorder comprising administering, to an individual in need of treatment, a therapeutically effective 15 amount of an optically active N-substituted aryl- or heteroaryl- cyclopropylamine, particularly a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof. In a more specific aspect, the disease or disorder is human disease or disorder chosen from cancer, depression, a neurodegenerative disease or disorder, or a viral infection. In one aspect, the neurodegenerative disease or disorder is Huntington disease, 20 Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In one aspect, the invention is a method of treating or preventing a disease or disorder comprising identifying an individual in need of treating or preventing and administering to 25 said individual a therapeutically effective amount of an optically active N-substituted aryl or heteroaryl- cyclopropylamine, particularly a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof. In a more specific aspect, the disease or disorder is human disease or disorder chosen from cancer, depression, a neurodegenerative disease or disorder, or a viral infection. In one aspect, the neurodegenerative disease or 30 disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.
WO 2012/013728 PCT/EP2011/062949 17 In one aspect, the invention provides a method for enriching an enantiomer of a trans N substituted cyclopropylamine (particularly of a compound of Formula (II) or (III), or of a compound of Formula (I) wherein the substituents on the cyclopropyl moiety are in trans orientation), the method comprising: 5 Contacting a trans-substituted cyclopropylamine with a chiral recrystallization agent in a solvent (particularly under conditions that are sufficient for the crystallization of the salt of the chiral recrystallization agent and the trans substituted cylopropylamine); and isolating the crystallized salt of the chiral recrystallization agent and the trans substituted 10 cyclopropylamine. In one aspect, the trans cyclopropylamine is an N-substituted aryl- or heteroaryl-cylopropylamine. In one aspect, the trans cyclopropylamine is 4 benzoxy-2 phenylcyclopropylamine or a derivative thereof wherein the amine is protected with a protecting group. 15 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including 20 definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. 25 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the identification of compounds and their use in treating and preventing diseases. The present invention provides compounds of Formula (I), 30 pharmaceutical compositions comprising a compound of Formula (I) or a phannaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, and their use for treating diseases. One use of the compounds of Formula (I) is for treating cancer. The compounds of Formula (I) can be used as LSD1 selective inhibitors that inhibit LSD1 to a WO 2012/013728 PCT/EP2011/062949 18 greater extent than MAO-A and MAO-B or as LSD1/MAO-B dual inhibitors that inhibit LSD1 and MAO-B to a greater extent than MAO-A. The compounds of Formula (I) as described herein are generally better inhibitors of LSD 1 by a factor of more than 10 to 20 or more as compared to tranylcypromine, with improved selectivity against MAO-A. Thus, 5 these compounds are LSD1 selective in that they inhibit LSD1 to an extent greater than MAO-A and MAO-B or are LSD1/MAO-B duals inhibitors that inhibit LSD1 and MAO-B to a greater extent than MAO-A. The present invention provides a compound of Formula (I) or a pharmaceutically acceptable 10 salt or solvate thereof: (B)-(A) N H \(D) (I) (A) is a cyclyl group having n substituents (R3). Preferably, (A) is an aryl group or a 15 heteroaryl group, wherein said aryl group or said heteroaryl group has n substituents (R3). More preferably, (A) is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, wherein (A) has n substituents (R3). Even more preferably, (A) is phenyl or pyridyl, wherein said phenyl or said pyridyl has n substituents (R3). In one embodiment, (A) has 0 or 1 substituent (R3). In a further embodiment, (A) has 0 substituents (R3). In a further 20 embodiment, (A) has I substituent (R3). It is to be understood that, if n is 0, the cyclyl group is not substituted with any substituents (R3) but may instead be substituted with hydrogen. (B) is a cyclyl group or an -(Ll)-cyclyl group, wherein said cyclyl group or the cyclyl 25 moiety comprised in said -(L1)-cyclyl group has n substituents (R2). Said cyclyl group or the cyclyl moiety comprised in said -(L1)-cyclyl group may, for example, be an aryl group (e.g., phenyl, naphthyl or anthracenyl) or a heteroaryl group (e.g., pyridinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, or pyrimidinyl). Preferably, (B) is -O-CH 2 -phenyl or phenyl, wherein 30 (B) has n substituents (R2). In one embodiment, (B) is phenyl having n substituents (R2). In a further embodiment, (B) is -O-CH 2 -phenyl having n substituents (R2). In one WO 2012/013728 PCT/EP2011/062949 19 embodiment, (B) has 0, 1 or 2 substituents (R2). In a further embodiment, (B) has 0 or 1 substituent (R2). In a further embodiment, (B) has 0 substituents (R2). In a further embodiment, (B) has 1 substituent (R2). 5 (LI) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene. Said alkylene may, e.g., be a straight-chain or branched chain alkylene having from 1 to 6 carbon atoms. Said heteroalkylene may, e.g., be a straight-chain or branched chain alkylene having from 1 to 6 carbon atoms, wherein 1, 2 (if present) or 3 (if present) carbon atoms are each replaced by a heteroatom selected independently from 0, N or S; accordingly, said heteroalkylene may, 10 e.g., be a straight-chain or branched chain alkylene having from 1 to 4 carbon atoms, wherein 1 or 2 non-adjacent carbon atoms are each replaced by 0. (D) is a heteroaryl group or a -(L2)-heteroaryl group, wherein said heteroaryl group or the heteroaryl moiety comprised in said -(L2)-heteroaryl group has one substituent (RI), and 15 further wherein said heteroaryl group is covalently bonded to the remainder of the molecule through a ring carbon atom or the heteroaryl moiety comprised in said -(L2)-heteroaryl group is covalently bonded to the (L2) moiety through a ring carbon atom. Preferably, (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl, wherein said thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, 20 thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl has one substituent (RI). In particular, (D) may be thiazolyl, oxadiazolyl or pyrimidinyl, wherein said thiazolyl, said oxadiazolyl or said pyrimidinyl has one substituent (RI). Most preferably, (D) is oxadiazolyl. 25 (L2) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene. Said alkylene may, e.g., be a straight-chain or branched chain alkylene having from 1 to 6 carbon atoms. Said heteroalkylene may, e.g., be a straight-chain or branched chain alkylene having from 1 to 6 carbon atoms, wherein 1, 2 (if present) or 3 (if present) carbon atoms are each replaced by a heteroatom selected independently from 0, N or S; accordingly, said heteroalkylene may, 30 e.g., be a straight-chain or branched chain alkylene having from 1 to 4 carbon atoms, wherein 1 or 2 non-adjacent carbon atoms are each replaced by 0.
WO 2012/013728 PCT/EP2011/062949 20 (RI) is a hydrogen bonding group. For example, (RI) may be -OH, -O(alkyl), -NH 2 , -NH(alkyl) (e.g., -NHCH 3 ), -N(alkyl)(alkyl) (e.g., -N(CH 3
)
2 ), amido, -SO-NH 2 , -SO-NH(alkyl), -SO-N(alkyl)(alkyl), -S(O) 2
NH
2 , -S(O) 2 NH(alkyl), -S(O) 2 N(alkyl)(alkyl),
-C(=O)NH
2 , -C(=O)NH(alkyl), -C(=O)N(alkyl)(alkyl), -alkylene-C(=O)NH 2 (e.g., 5 -CH 2
-C(=O)NH
2 ), -alkylene-C(=O)NH(alkyl) (e.g., -CH 2 -C(=O)NH(alkyl)), -alkylene-C(=O)N(alkyl)(alkyl) (e.g., -CH 2 -C(=O)N(alkyl)(alkyl)), -NHC(=O)-alkyl (e.g.,
-NHC(=O)CH
3 ), -N(alkyl)-C(=O)-alkyl (e.g., -N(-CH 3
)-C(=O)CH
3 ), -alkylene-NH 2 (e.g.,
-CH
2
-NH
2 ), -alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl), wherein it is preferred that the aforementioned alkyl and alkylene groups each independently have from 1 to 6 carbon 10 atoms. Preferably, (RI) is -OH, -NH 2 , amido, -S(O) 2
NH
2 , -C(=0)NH 2 , -CH 2
-C(=O)NH
2 , NHC(=O)CH 3 , -NHCH 3 , -N(CH 3
)
2 or -CH 2
-NH
2 , particularly -OH, -NH 2 , -NHCH 3 , amido,
-S(O)
2
NH
2 , -C(=O)NH 2 , -CH 2
-C(=O)NH
2 , or -CH 2
-NH
2 . More preferably, (RI) is -NH 2 or
-NHCH
3 . Even more preferably, (RI) is -NH 2 . 15 Each (R2) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. For example, each (R2) may be independently selected from hydroxyl, halo (e.g., -Cl or -F) or haloalkyl (e.g., -CF 3 ). Accordingly, each (R2) may, for example, be selected independently from hydroxyl or 20 haloalkyl (e.g., -CF 3 ). It is preferred that each (R2) is halo, more preferably -F. Each (R3) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea. For example, each (R3) may be 25 independently selected from alkyl, cyclyl, amino, amido, alkylamino, hydroxyl, halo, haloalkyl, haloalkoxy, cyano, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea. n is independently 0, 1, 2, 3 or 4. For example, each n may be independently 0, 1 or 2. In particular, each n may be independently 0 or 1. 30 The substituents of the cyclopropyl moiety, i.e., the (A) group and the -NH-CH 2 -(D) group, are preferably in trans-configuration.
WO 2012/013728 PCT/EP2011/062949 21 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (I) wherein (A) is an aryl or heterocyclyl. In a more preferred embodiment (A) is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl. In an even more preferred embodiment (A) is phenyl or pyridinyl. 5 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (I) wherein, (B) is a -L2-cyclyl. In a more preferred embodiment (B) is -0-phenyl or -O-CH 2 -phenyl. In an even more preferred embodiment (B) is -O-CH 2 -phenyl. In one specific embodiment the phenyl group of said (B) group has 1, 2, 3, or 4 optional 10 substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. In one preferred embodiment of the first aspect, the invention provides a compound of 15 Formula (I) wherein, (B) is cyclyl. In a more preferred embodiment (B) is phenyl. In one specific embodiment, the phenyl group of said (B) group has 1, 2, 3, or 4 optional substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. 20 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (I), wherein (R2) is hydroxyl, halo or haloalkyl. In one preferred embodiment (R2) is -OH or -CF 3 . In another preferred embodiment (R2) is fluoro or chloro. 25 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (I), wherein (D) is a monocyclic heteroaryl. In a more preferred embodiment (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl. In one specific embodiment, said cyclyl (D) has one substituent (RI). 30 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (I) wherein (RI) is a hydrogen bonding group. For example, (RI) may be -OH, O(alkyl), -NH 2 , -NH(alkyl) (e.g., -NHCH 3 ), -N(alkyl)(alkyl), amido, -SO-NH 2 , -SO- WO 2012/013728 PCT/EP2011/062949 22 NH(alkyl), -SO-N(alkyl)(alkyl), -S(O) 2
NH
2 , -S(O) 2 NH(alkyl), -S(O) 2 N(alkyl)(alkyl), -C(=0)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl)(alkyl), -alkylene-C(=O)NH 2 (e.g., -CH 2 C(=0)NH 2 ), -alkylene-C(=O)NH(alkyl) (e.g., -CH 2 -C(=O)NH(alkyl)), -alkylene-C(=O)N(alkyl)(alkyl) (e.g., -CH 2 -C(=O)N(alkyl)(alkyl)), -NHC(=O)-alkyl (e.g., 5 -NHC(=O)CH 3 ), -N(alkyl)-C(=O)-alkyl (e.g., -N(-CH 3
)-C(=O)CH
3 ), -alkylene-NH 2 (e.g., CH 2
-NH
2 ), -alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl), wherein it is preferred that the aforementioned alkyl and alkylene groups each independently have from 1 to 6 carbon atoms. In a more preferred embodiment (RI) is a -NH 2 , -OH, amido, -NHC(=O)CH 3 , NHCH 3 or -S(O) 2
NH
2 . In an even more preferred embodiment (RI) is -NH 2 . 10 The compound of Formula (I) as described and defined herein may, for example, be a compound of the following Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof: (B) (A) NH (D) Rn (R3)n1 15 (R2) R) (Ia) wherein (A), (B), (D), (RI), (R2), (R3) and n have the meanings or the preferred meanings described herein for the compound of Formula (I). 20 Preferably, the compounds of the invention, including in particular the compounds of Formula (I), (Ia) or (Ib) as described herein, are used to treat a disease in a mammal and more preferably a human. More preferably, the human disease is chosen from cancer (e.g., breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, 25 blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma, or myeloma), a neurological condition or disease (e.g., depression, Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic WO 2012/013728 PCT/EP2011/062949 23 Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies), or a viral infection. In one preferred embodiment of the first aspect, the invention provides a compound of 5 Formula (Ia) wherein (A) is aryl or heterocyclyl. In a more preferred embodiment (A) is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, and thiazolyl. In an even more preferred embodiment (A) is a phenyl or a pyridinyl. In one preferred embodiment of the first aspect, the invention provides a compound of 10 Formula (Ia) wherein (B) is -L2-cyclyl. In a more preferred embodiment (B) is -0-phenyl or -O-CH 2 -phenyl. In an even more preferred embodiment (B) is -O-CH 2 -phenyl. In one specific embodiment the phenyl group of said (B) group has 1, 2, 3, or 4 optional substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, 15 sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. In one preferred embodiment of the first aspect, the invention provides a compound of Formula (Ia) wherein (B) is cyclyl. In a more preferred embodiment (B) is phenyl. In one specific embodiment the phenyl group of said (B) group has 1, 2, 3, or 4 optional 20 substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. In one preferred embodiment of the first aspect, the invention provides a compound of 25 Formula (Ia) wherein (R2) is hydroxyl, halo or haloalkyl. In one preferred embodiment (R2) is -OH or -CF 3 . In another preferred embodiment (R2) is fluoro or chloro. In one preferred embodiment of the first aspect, the invention provides a compound of Formula (Ia), wherein (D) is a monocyclic heteroaryl. In a more preferred embodiment (D) 30 is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl. In one specific embodiment said cyclyl (D) has one substituent
(RI).
WO 2012/013728 PCT/EP2011/062949 24 In one preferred embodiment of the first aspect, the invention provides a compound of Formula (Ia) wherein (RI) is a hydrogen bonding group. For example, (RI) may be -OH, O(alkyl), -NH 2 , -NH(alkyl) (e.g., -NHCH 3 ), -N(alkyl)(alkyl), amido, -SO-NH 2 , -SO NH(alkyl), -SO-N(alkyl)(alkyl), -S(O) 2
NH
2 , -S(O) 2 NH(alkyl), -S(O) 2 N(alkyl)(alkyl), 5 -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl)(alkyl), -alkylene-C(=O)NH 2 (e.g., -CH 2 C(=O)NH 2 ), -alkylene-C(=O)NH(alkyl) (e.g., -CH 2 -C(=O)NH(alkyl)), -alkylene-C(=O)N(alkyl)(alkyl) (e.g., -CH 2 -C(=O)N(alkyl)(alkyl)), -NHC(=O)-alkyl (e.g.,
-NHC(=O)CH
3 ), -N(alkyl)-C(=O)-alkyl (e.g., -N(-CH 3
)-C(=O)CH
3 ), -alkylene-NH 2 (e.g., CH 2
-NH
2 ), -alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl), wherein it is preferred that 10 the aforementioned alkyl and alkylene groups each independently have from 1 to 6 carbon atoms. In a more preferred embodiment (RI) is a -NH 2 , -OH, amido, -NHC(=O)CH 3 , NHCH 3 or -S(O) 2
NH
2 . In a more preferred embodiment (RI) is a -NH 2 , -OH, amido, or S(O) 2
NH
2 . In an even more preferred embodiment (RI) is -NH 2 . 15 Thus in a preferred aspect, the invention provides a compound of Formula (Ib) or a pharmaceutically acceptable salt or solvate thereof or its use in treating or preventing a disease or disorder: (B) (A) NH (D)
(R
3 )n (R2)n 20 (R 1 ) (Ib) wherein: (A) is a phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl group having n optional 25 substituents (R3); (B) is -O-CH 2 -phenyl or phenyl, wherein the phenyl group has n optional substituents (R2); (D) is thiazolyl, oxadiazolyl or pyrimidinyl wherein said (D) has one substituent (RI); (RI) is -NH 2 , -OH, amido, -NHC(=O)CH 3 , -NHCH 3 or -S(O) 2
NH
2
;
WO 2012/013728 PCT/EP2011/062949 25 each (R2) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea; each (R3) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C 5 amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and n is independently 1, 2, 3 or 4. In one embodiment of this aspect, the compound of Formula (Tb) is used to treat a disease in 10 a mammal and more preferably a human. In another embodiment, the disease or disorder is chosen from cancer, a neurological condition or disease, or a viral infection. In one embodiment, the neurological disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia. 15 In another embodiment of this aspect, the disease or disorder is cancer. In another embodiment the cancer is prostate cancer. In another specific embodiment of this aspect the cancer is breast cancer. In another yet specific embodiment of this aspect the cancer is lung cancer. In another yet specific embodiment of this aspect the cancer is colorectal cancer. In another yet specific embodiment of this aspect the cancer is brain cancer. In another yet 20 specific embodiment of this aspect the cancer is skin cancer. In another yet specific embodiment of this aspect the cancer is blood cancer (e.g., leukemia, including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), a lymphoma, 25 or myeloma. In another specific embodiment of this aspect, the invention provides a compound of Formula (Ib) for use in treating or preventing a disease or disorder wherein (A) is aryl or heterocyclyl. In a more preferred embodiment (A) is phenyl, pyridinyl, thiophenyl, 30 pyrrolyl, furanyl, or thiazolyl. In an even more preferred embodiment (A) is phenyl or pyridinyl.
WO 2012/013728 PCT/EP2011/062949 26 In another specific embodiment of this aspect, the invention provides a compound of Formula (Ib) for use in treating or preventing a disease or disorder wherein (B) is -L2 cyclyl. In a more preferred embodiment (B) is -0-phenyl or -O-CH 2 -phenyl. In an even more preferred embodiment (B) is -O-CH 2 -phenyl. In one specific embodiment the phenyl 5 group of said (B) group has 1, 2, 3, or 4 optional substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. 10 In another specific embodiment of this aspect, the invention provides a compound of Formula (Ib) for use in treating or preventing a disease or disorder wherein (B) is cyclyl. In a more preferred embodiment (B) is phenyl. In one specific embodiment the phenyl group of said (B) group has 1, 2, 3, or 4 optional substituents (R2) independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, 15 haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea. In another specific embodiment of this aspect, the invention provides a compound of Formula (Ib) for use in treating or preventing a disease or disorder wherein (R2) is 20 hydroxyl, halo or haloalkyl. In one preferred embodiment (R2) is -OH or -CF 3 . In another preferred embodiment (R2) is fluoro or chloro. In another specific embodiment of this aspect, the invention provides a compound of Formula (Ib) for use in treating or preventing a disease or disorder wherein (D) is a 25 monocyclic heteroaryl. In a more preferred embodiment (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl. In one specific embodiment said cyclyl (D) has one substituent (RI). In another specific embodiment of this aspect, the invention provides a compound of 30 Formula (Ib) for use in treating or preventing a disease or disorder wherein (RI) is a hydrogen bonding group. For example, (RI) may be -OH, -O(alkyl), -NH 2 , -NH(alkyl) (e.g., -NHCH 3 ), -N(alkyl)(alkyl), amido, -SO-NH 2 , -SO-NH(alkyl), -SO-N(alkyl)(alkyl),
-S(O)
2
NH
2 , -S(O) 2 NH(alkyl), -S(O) 2 N(alkyl)(alkyl), -C(=O)NH 2 , -C(=O)NH(alkyl), WO 2012/013728 PCT/EP2011/062949 27 -C(=O)N(alkyl)(alkyl), -alkylene-C(=O)NH 2 (e.g., -CH 2
-C(=O)NH
2 ), -alkylene C(=O)NH(alkyl) (e.g., -CH 2 -C(=O)NH(alkyl)), -alkylene-C(=O)N(alkyl)(alkyl) (e.g.,
-CH
2 -C(=O)N(alkyl)(alkyl)), -NHC(=O)-alkyl (e.g., -NHC(=O)CH 3 ), -N(alkyl)-C(=O) alkyl (e.g., -N(-CH 3
)-C(=O)CH
3 ), -alkylene-NH 2 (e.g., -CH 2
-NH
2 ), -alkylene-NH(alkyl), or 5 -alkylene-N(alkyl)(alkyl), wherein it is preferred that the aforementioned alkyl and alkylene groups each independently have from 1 to 6 carbon atoms. In a more preferred embodiment (RI) is -NH 2 , -OH, amido, -NHC(=O)CH 3 , -NHCH 3 or -S(O) 2
NH
2 . In an even more preferred embodiment (RI) is -NH 2 . 10 In one aspect, the invention provides a stereoisomer or a mixture thereof, of a compound of Formula (I), (Ia) or (Ib). In another aspect, the invention relates to a derivative or analog of a compound of Formula (I), (Ia) or (Tb). 15 In yet another aspect, the invention relates to a solvate or polymorph of a compound of Formula (I), (Ia) or (Tb). In yet another aspect, the invention relates to a prodrug of a compound of Formula (I), (Ia) 20 or (Ib). In yet another aspect, the invention relates to a metabolite of a compound of Formula (I), (Ia) or (Ib). 25 In another aspect, the invention provides a method of treating or preventing a disease or condition comprising administering, to a patient (preferable human) in need of treatment or prevention, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (Ia) or (Tb) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. This aspect can be 30 reformulated as a compound of Formula (I), (Ia) or (Tb) for use as a medicine. In a related aspect, the invention provides a pharmaceutical composition for use in treating or preventing a disease or condition wherein said composition comprises a therapeutically effective amount of a compound of Formula (I), (Ia) or (Tb) sufficient for treating or WO 2012/013728 PCT/EP2011/062949 28 preventing said disease or condition. In a more specific embodiment the invention provides a compound of Formula (I), (Ia) or (Ib) for use in the treatment of a disease associated with LSD1. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the 5 therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. 10 In yet another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula (I), (Ia) or (Ib) and a pharmaceutically acceptable carrier. In a more specific aspect, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib). In an even more specific aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount 15 effective to inhibit LSD 1. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount sufficient to modulate the level of histone 3 lysine 4 methylation. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 20 lysine-9 methylation levels. In again another aspect, the invention provides a method of inhibiting LSD1 activity comprising administering, to a patient in need of treatment, a therapeutically effective amount of a composition comprising a compound of Formula (I), (Ia) or (Ib) or a 25 pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier sufficient to inhibit LSD1 activity. This aspect can be reformulated as a compound of Formula (I), (Ia) or (Ib) as herein defined for use as a LSD1 inhibitor. This aspect can also be reformulated as a compound of Formula (I), (Ia) or (Ib) for the manufacture of a medicament for the treatment of a disease associated to LSD 1. In a related aspect, a method 30 for treating an individual is provided, said method comprising identifying an individual in need of treatment and administering to said individual a therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib). In a preferred aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount sufficient to inhibit LSD1.
WO 2012/013728 PCT/EP2011/062949 29 In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount sufficient to modulate the level of histone 4 lysine 3 methylation. In another preferred aspect, the 5 therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. Preferred embodiments of the compounds of Formula (I), (Ia) or (Ib) for use in the composition and method of this four aspect of the invention are as defined herein above in 10 the first aspect of the invention. In still another aspect, the invention provides a method of treating or preventing cancer comprising administering, to a patient in need of treatment, a therapeutically effective amount of a composition comprising a compound of Formula (I), (Ia) or (Ib) as defined 15 above in the first aspect of the invention, and a pharmaceutically acceptable carrier. This aspect can be reformulated as a compound of Formula (I), (Ia) or (Tb) as defined above in the first aspect of the invention for use in the treatment or prevention of cancer. In a related aspect, the invention provides a pharmaceutical composition for use in treating or preventing cancer wherein said composition comprises a therapeutically effective amount of 20 a compound of Formula (I), (Ia) or (Ib) sufficient for treating or preventing cancer. In another related aspect, the invention provides a compound of Formula (I), (Ia) or (Tb) or a pharmaceutical composition for the treatment or prevention of a cancer wherein said cancer is chosen from testicular cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer (e.g., leukemia, including, for example, acute 25 myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma and myeloma, wherein said composition comprises a therapeutically effective amount of a compound of Formula (I), (Ia) or (Tb) sufficient for treating or preventing the said cancer. In a preferred aspect, the 30 therapeutically effective amount of a compound of Formula (I), (Ia) or (Tb) is an amount sufficient to inhibit LSD 1. in another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone methylation levels. In another preferred aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Tb) is an amount WO 2012/013728 PCT/EP2011/062949 30 sufficient to modulate the level of histone-3 lysine-4 methylation. In another preferred aspect, the therapeutically effective amount is an amount sufficient to modulate histone-3 lysine-9 methylation levels. 5 In still another aspect, the invention provides a method of treating or preventing a neurological disease or disorder comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of a composition comprising a compound of Formula (I), (Ia) or (Tb) as defined above in the first aspect of the invention, and a pharmaceutically acceptable carrier. This aspect can be reformulated as a compound of 10 Formula (I), (Ia) or (Tb) as defined above in the first aspect of the invention for use in the treatment or prevention of a neurological disease or disorder. In a related aspect, the invention provides a pharmaceutical composition for use in treating or preventing a neurological disease or disorder wherein said composition comprises a therapeutically effective amount of a compound of Formula (I), (Ta) or (Ib) sufficient for treating or 15 preventing a neurological disease or disorder. In another related aspect, the invention provides a compound of Formula (I), (Ia) or (Ib) or a pharmaceutical composition for the treatment or prevention of a neurological disease or disorder wherein said neurological disease or disorder chosen from Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia, or Dementia with Lewy 20 Bodies, and further wherein said composition preferably comprises a therapeutically effective amount of the compound of Formula (I), (Ia) or (Ib) sufficient for treating or preventing the said neurological disease or disorder. In a preferred aspect, the therapeutically effective amount of a compound of Formula (I), (Ia) or (Ib) is an amount sufficient to inhibit LSD 1. In another preferred aspect, the therapeutically effective amount 25 of a compound of Formula (I), (Ta) or (Ib) is an amount sufficient to modulate the level of histone-3 lysine-4 methylation In a still yet aspect, the invention provides a method for identifying a compound which is a selective inhibitor of LSD1, the method comprising selecting or providing a compound of 30 Formula (I) and determining the ability of the said compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor. Thus, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a WO 2012/013728 PCT/EP2011/062949 31 compound of Formula (I), (Ia) or (Ib) which is a selective inhibitor of LSD1. LSD1 selective inhibitors have Ki (IC50) values for LSD1 which are lower than the Ki (IC50) value for MAO-A and/or MAO-B. Preferably, the Ki (IC50) values for LSD1 are two-fold lower than for MAO-A and/or MAO-B. In one aspect of this embodiment, the LSD1 Ki 5 value is at least 5-fold lower than the Ki (IC50) value for MAO-A and/or MAO-B. In one aspect of this embodiment, the LSD1 Ki (IC50) value is at least 10-fold lower than the Ki (IC50) value for MAO-A and/or MAO-B. In one embodiment of this aspect of the invention, the pharmaceutical composition comprising a LSD1 selective inhibitor of Formula (I), (Ta) or (Tb) or a pharmaceutically acceptable salt or solvate thereof is useful for 10 treating and/or preventing a disease in an individual. In one specific embodiment, a therapeutically effective amount of the composition is administered to an individual in an amount sufficient to prevent or treat a disease or disorder. In a more specific, the disease is cancer, a neurological disease or condition, or a viral infection. In an even more specific aspect, the disease is a cancer chosen from prostate, testicular, brain, colorectal, lung, breast, 15 skin, and blood cancer. In another aspect, the neurological disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In a still yet aspect, the invention provides a method for identifying a compound which is a 20 dual inhibitor of LSD1 and MAO-B, the method comprising selecting or providing a compound of Formula (I) and determining the ability of the said compound to inhibit LSD 1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 and MAOB to a greater extent than MAO-A is identified as a LSD1/MAO-B dual inhibitor. Thus, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable 25 carrier and a compound of Formula (I), (Ia) or (Tb) which is a dual inhibitor of LSD1/MAO B. LSD1/MAO-B dual inhibitors have Ki (IC50) values for LSD1 and MAO-B which are lower than the Ki (IC50) value for MAO-A. Preferably, the Ki (IC50) values for LSD1 and MAO-B are two-fold lower than for MAO-A. In one aspect of this embodiment, the LSD 1/MAO-B dual inhibitors have Ki (IC50) values at least 5-fold lower than the Ki (IC50) 30 value for MAO-A. In one aspect of this embodiment, the LSD1/MAO-B Ki (IC50) values are at least 10-fold lower than the Ki (IC50) value for MAO-A. In one embodiment of this aspect of the invention, the pharmaceutical composition comprising a LSD1/MAO-B dual inhibitor of Formula (I), (Ia) or (Tb) or a pharmaceutically acceptable salt or solvate thereof WO 2012/013728 PCT/EP2011/062949 32 is useful for treating and/or preventing a disease in an individual. In one specific embodiment, a therapeutically effective amount of the composition is administered to an individual in an amount sufficient to prevent or treat a disease or disorder. In a more specific, the disease is cancer, a neurological disease or condition, or a viral infection. In an 5 even more specific aspect, the disease is a cancer chosen from prostate, testicular, brain, colorectal, lung, breast, skin, and blood cancer. In another aspect, the neurological disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. 10 Recent studies have implicated LSD 1 in viral infection and reactivation. In particular it was shown that pharmacological inhibitors of LSD1 like parnate and siRNA knock down of LSD1 caused reduced viral infectivity and reduced reactivation after latency (Liang et al. (2009) Nat. Med. 15:1312-1317). Therefore it is believed that the compounds of the invention can be used for treating or preventing viral infection. Furthermore, it is believed 15 that the compounds of the invention can treat or prevent viral reactivation after latency. Thus, in another aspect, the invention provides a method for treating or preventing a viral infection, the method comprising administering to an individual (preferably a human) a compound of Formula (I), (Ia) or (Tb) as defined above in any of the aspects and 20 embodiments of the invention or a pharmaceutically acceptable salt or solvate thereof. Accordingly, the invention also provides a compound of Formula (I), (Ia) or (Tb) as defined above in any of the aspects and embodiments of the invention or a pharmaceutically acceptable salt or solvate thereof for use in treating or preventing a viral infection. In one specific embodiment, the viral infection is a herpesvirus infection. In a more specific 25 embodiment, the herpesvirus infection is caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, and Epstein-Barr virus. In another embodiment of this seventh aspect, the viral infection is caused by and/or associated with HIV. In an even more specific embodiment, the invention provides a method for treating or preventing viral reactivation after latency, the method comprising administering to an individual (preferably 30 a human) a compound of Formula (I), (Ia) or (Tb) as defined above in any of the aspects and embodiments of the invention or a pharmaceutically acceptable salt or solvate thereof. Accordingly, the invention also provides a compound of Formula (I), (Ta) or (Tb) as defined above in any of the aspects and embodiments of the invention or a pharmaceutically WO 2012/013728 PCT/EP2011/062949 33 acceptable salt or solvate thereof for use in treating or preventing viral reactivation after latency. In a specific embodiment, the virus that is reactivating is a herpesvirus. In a more specific embodiment, the herpesvirus that is reactivating is chosen from HSV-1, HSV-2, and Epstein-Barr virus. In an even more specific embodiment, the virus that is reactivating is 5 HSV. During the inventors' investigation of amine oxidases like LSD1, MAO-B and MAO-A, it was unexpectedly found that the stereochemical configuration of the cyclopropyl carbons of N-substituted arylcyclopropylamine compounds substantially affects the potency of LSD1 10 inhibition. The inventors have shown that the (-) stereoisomer of 5-(((trans)-2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine is about 20-fold more active against LSD1 than the corresponding (+) stereoisomer. Furthermore, the (-) stereoisomer retained substantial MAO-B inhibitory activity. Notably, the selectivity for LSD1/MAO-A for the (-)/(+) stereoisomer was over 100 fold as judged by kinact/K1 values. 15 Thus, (-) stereoisomers of the compounds of the present invention, including particularly the compounds of Formula (I), (Ia) and (Ib), are unexpectedly potent LSD1 inhibitors compared to their respective enantiomers. The invention thus relates to a compound of Formula (I), (Ia) or (Ib) as described and defined herein, wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are in trans-configuration and 20 further wherein the compound is optically active. The invention, in one aspect, relates to a substantially pure, optically active stereoisomer of a compound of Formula (I), (Ia) or (Ib) as described and defined herein, wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are 25 in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, as well as its use in as a medicament. In a specific aspect, the substantially pure, optically active stereoisomer of a compound of Formula (I), (Ia) or (Tb), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are in trans configuration, is 90 mole-% or greater (-) stereoisomer and 10 mole-% or less (+) 30 stereoisomer. In a more specific aspect, the substantially pure, optically active stereoisomer is 95 mole-% or greater (-) stereoisomer and 5 mole-% or less (+) stereoisomer. In yet a more specific aspect, the substantially pure, optically active stereoisomer is 98 mole-% or greater (-) stereoisomer and 2 mole-% or less (+) stereoisomer. In an even more specific WO 2012/013728 PCT/EP2011/062949 34 aspect, the substantially pure, optically active stereoisomer is 99 mole-% or greater (-) stereoisomer and 1 mole-% or less (+) stereoisomer. In yet an even more specific aspect, the substantially pure stereoisomer is 99.5 mole-% or greater (-) stereoisomer and 0.5 mole % or less (+) stereoisomer. The substantially pure, optically active stereoisomer of a 5 compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are in trans-configuration, is useful in treating or preventing a disease or disorder, particularly cancer, depression, a neurodegenerative disease or disorder, or a viral infection. 10 The invention also relates to a composition comprising a stereoisomer of a compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the compound. In a specific aspect said 15 composition has a 95% or more enantiomeric excess of the (-) stereoisomer of the compound. In a more specific aspect said composition has a 98% or more enantiomeric excess of the (-) stereoisomer of the compound. In an even more specific aspect said composition has a 99% or more enantiomeric excess of the (-) stereoisomer of the compound. The composition, in one aspect, is for use in treating or preventing a disease or 20 disorder, particularly cancer, depression, or a neurodegenerative disease or disorder, or a viral infection. Accordingly, the invention relates to a compound of Formula (I), (Ia) or (Tb), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are 25 in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, wherein the (-) stereoisomer of said compound is present at an enantiomeric excess of 90% or more, preferably of 95% or more, more preferably of 98% or more, and even more preferably of 99% or more. 30 In a further aspect, the invention relates to a pharmaceutical composition comprising a stereoisomer of a compound of Formula (I), (Ia) or (Tb), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group -NH-CH 2 -(D)) are in trans configuration, or a pharmaceutically acceptable salt or solvate thereof, and a WO 2012/013728 PCT/EP2011/062949 35 pharmaceutically acceptable carrier, wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the compound. In a specific aspect said composition has a 95% or more enantiomeric excess of the (-) stereoisomer of the compound. In a specific aspect said composition has a 99% or more enantiomeric excess of 5 the (-) stereoisomer of the compound. The pharmaceutical composition of this aspect is particularly useful in treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection. In one aspect, the invention relates to an optically active compound of Formula (I), (Ia) or 10 (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group
-NH-CH
2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising any of the aforementioned compounds, wherein said compound is the (1 R, 2S) enantiomer (in respect to the substituents on the cyclopropyl ring) substantially free of the (lS, 2R) enantiomer. Preferably, the compound is more than 90 15 mole-% (IR, 2S) enantiomer and less than 10 mole-% (1S, 2R) enantiomer. More preferably, the compound is more than 95 mole-% (1R, 2S) enantiomer and less than 5 mole-% (1S, 2R) enantiomer. Yet more preferably, the compound is more than 98 mole-% (1R, 2S) enantiomer and less than 2 mole-% (lS, 2R) enantiomer. Even yet more preferably, the compound is more than 99 mole-% (1R, 2S) enantiomer and less than 1 20 mole-% (1S, 2R) enantiomer. Still even more preferably, the compound is more than 99.5 mole-% (1R, 2S) enantiomer and less than 0.5 mole-% (IS, 2R) enantiomer. The enantiomeric content can be determined, for example, by chiral HPLC (e.g., as described in Example 36). 25 In one aspect, the invention relates to an optically active compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group NH-CH 2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising any of the aforementioned compounds, wherein said compound is the (1S, 2R) enantiomer (in respect to the substituents on the cyclopropyl ring) 30 substantially free of the (1R, 2S) enantiomer. Preferably, the compound is more than 90 mole-% (1S, 2R) enantiomer and less than 10 mole-% (IR, 2S) enantiomer. More preferably, the compound is more than 95 mole-% (iS, 2R) enantiomer and less than 5 mole-% (IR, 2S) enantiomer. Yet more preferably, the compound is more than 98 mole-% WO 2012/013728 PCT/EP2011/062949 36 (IS, 2R) enantiomer and less than 2 mole-% (IR, 2S) enantiomer. Even yet more preferably, the compound is more than 99 mole-% (IS, 2R) enantiomer and less than 1 mole-% (lR, 2S) enantiomer. Still even more preferably, the compound is more than 99.5 mole-% (1S, 2R) enantiomer and less than 0.5 mole-% (lR, 2S) enantiomer. The 5 enantiomeric content can be determined, for example, by chiral HPLC (e.g., as described in Example 36). In one aspect, the invention relates to an optically active compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group 10 -NH-CH 2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl ring carbon atom which is bound to the amino group of the compound has the (S)-configuration and the cyclopropyl ring carbon atom which is bound to the cyclic group (A) attached to the cyclopropyl ring of the compound has the (R)-configuration. Preferably, the compound is provided in an enantiomeric excess of at 15 least 90%. Even more preferably the compound is provided in an enantiomeric excess of at least 95%. Yet still more preferably the compound is provided in an enantiomeric excess of at least 98%. Still more preferably the compound is provided in an enantiomeric excess of at least 99%. The enantiomeric excess can be determined, for example, by chiral HPLC (e.g., as described in Example 36). 20 In one aspect, the invention relates to an optically active compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group
-NH-CH
2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl ring carbon atom which is bound to the amino group of the 25 compound has the (R)-configuration and the cyclopropyl ring carbon atom which is bound to the cyclic group (A) attached to the cyclopropyl ring of the compound has the (S)-configuration. Preferably, the compound is provided in an enantiomeric excess of at least 90%. Even more preferably the compound is provided in an enantiomeric excess of at least 95%. Yet still more preferably the compound is provided in an enantiomeric excess of 30 at least 98%. Still more preferably the compound is provided in an enantiomeric excess of at least 99%. The enantiomeric excess can be determined, for example, by chiral HPLC (e.g., as described in Example 36).
WO 2012/013728 PCT/EP2011/062949 37 In one aspect, the invention relates to an optically active compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group
-NH-CH
2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a disease or disorder, such as, e.g., cancer, a 5 neurological disease, disorder or condition, or a viral infection. In one aspect, the neurological disease, disorder or condition is depression, Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In one specific aspect, the cancer is prostate cancer. In another specific, the cancer is breast cancer. In another aspect, the cancer is lung cancer. In 10 another aspect, the cancer is colorectal cancer. In another specific aspect, the cancer is brain cancer. In another specific aspect, the cancer is skin cancer. In another specific aspect, the cancer is blood cancer (e.g., a leukemia or a lymphoma; the leukemia to be treated or prevented includes, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic 15 leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia). In one aspect, the neurological disease, disorder or condition is depression, Huntington disease, Parkinson disease, or Alzheimer disease. In one aspect, the viral infection is an infection with HSV1 or HSV2. In one aspect, the disease or disorder is depression. In one aspect, the neurological disease, disorder or condition is a 20 neurodegenerative disease, disorder or condition. In one aspect, the neurodegenerative disease. disorder or condition is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia. The invention further relates to the optically active compound of Formula (I), (Ia) or (Ib), 25 wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group
-NH-CH
2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate thereof, as defined in any of the above embodiments or aspects, for use in the treatment or prevention of a disease or disorder, in particular cancer (e.g., breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia 30 (including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma, or myeloma), a neurological disease or condition (e.g., depression, Alzheimer's WO 2012/013728 PCT/EP2011/062949 38 disease, Huntington disease, Parkinson's disease, or Dementia with Lewy Bodies), or a viral infection (e.g., a viral infection is caused by and/or associated with HIV, or a herpesvirus infection, such as a herpesvirus infection caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, or Epstein-Barr virus) in a subject (preferably a mammal, 5 more preferably a human). The invention further relates to the optically active compound of Formula (I), (Ia) or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., the group (A) and the group
-NH-CH
2 -(D)) are in trans-configuration, or a pharmaceutically acceptable salt or solvate 10 thereof, as defined in any of the above embodiments or aspects, for use in the treatment or prevention of a disease or disorder wherein said disease or disorder is a neurodegenerative disease or disorder. In one aspect, the neurodegenerative disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia. 15 In another preferred aspect, the invention is an optically active N-substituted aryl- or heteroaryl cyclopropylamine, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treating or preventing a disease or disorder. Preferably, the optically active N-substituted aryl- or heteroaryl cyclopropylamine, as described herein, is a compound of 20 Formula (II) or a pharmaceutically acceptable salt or solvate thereof: Ri1 -(A")-R2" (II) 25 wherein: (A") is an aryl or heteroaryl group having 2 substituents, Rln and R2", and 1, 2, or 3 optional substituents independently chosen from halo, Cl -C3 alkyl, or Cl -C3 alkoxy; 30 R1 is an -Li-R3" group; WO 2012/013728 PCT/EP2011/062949 39 R3" is an aryl or heterocyclyl group having 1, 2, 3, 4, or 5 optional substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is a Cl -C6 alkyl or phenyl; 5 L 1 1 is chosen from a bond, -CH 2 0-, -CH 2
CH
2 0-, - OCH 2 -, - OCH 2
CH
2 -, -CH 2 -, -CH 2
CH
2 -,
-CH
2
CH
2
CH
2 -, or -0-; R2" is -Cyclopropyl-NH-L 2 -R4 wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (All) and -NH 10 L 2 11 -R4" are covalently attached; R4r is a 5 or 6 membered heteroaryl ring having 1, 2, or 3 optional substituents independently chosen from alkyl, -NH-R B, -ORB, or halo wherein RB is hydrogen, Cl-C3 alkyl, or -C(=O)CH 3 ; 15
L
2 r1 is a branched or unbranched Cl -C4 alkylene group and wherein said compound of Formula (II) is optically active. 20 Optically active compounds for use in the methods of the invention and optically active compounds of the invention refer to enriched stereoisomers of compounds wherein the enrichment is in reference to the chiral centers corresponding to the enantiomers of the trans-substituted cyclopropyl moiety. Other chiral centers may or may not be present in the molecule and the configuration or optical rotation attributable to these centers are not 25 intended to be addressed by this invention e.g., their effect on LSD 1, MAO-A, or MAO-B. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (1I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 30 carrier. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (II) as defined above, or a WO 2012/013728 PCT/EP2011/062949 40 pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or disorder. Preferably, the optically active N-substituted aryl- or heteroaryl cyclopropylamine, or 5 pharmaceutically acceptable salt or solvate thereof, for use in a method of treating or preventing a disease or disorder, as described herein, is of Formula (II): Rl"-(A")-R2" (II) 10 wherein: (A") is an aryl or heteroaryl group having 2 substituents, Rl" and R2", and 1, 2, or 3 optional substituents independently chosen from halo, C1-C3 alkyl, or C1-C3 alkoxy; 15 RI" is an -Lir"-R3" group; R3" is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2, or 3 optional substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 20 wherein RA is Cl-C6 alkyl or phenyl; Lil is chosen from a bond,-CH 2 0-, or -CH 2 0-; R2r is -Cyclopropyl-NH-L 2 r-R4" wherein said cyclopropyl group has two chiral centers 25 substituted in the trans orientation corresponding to the carbons to which (A") and -NH L2n'-R4r are covalently attached; R4" is a 5-membered heteroaryl ring having 1, 2, or 3 optional substituents independently chosen from -NH 2 or -NH(C 1 -C3) alkyl; 30
L
2 11 is -CH 2 - or -CH 2
CH
2 -; and wherein said compound of Formula (II) is optically active.
WO 2012/013728 PCT/EP2011/062949 41 The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl-cyclopropylamine of Formula (II) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 5 carrier. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (II) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 10 carrier, for use in treating or preventing a disease or disorder. Furthermore, the inventors have unexpectedly found that a subset of optically active compounds of Formula (II) as shown in Formula (III) are potent and selective inhibitors of LSD1 or LSD1 and MAO-B. 15 The invention therefore is an optically active compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof: Rll"-(A"')-R2"1 20 (III) wherein: (A"') is an aryl or heteroaryl group having 2 substituents, R1"' and R2"', and 1, 2, or 3 25 optional substituents wherein said optional substituents are independently chosen from halo, Cl-C3 alkyl, or C1-C3 alkoxy; R1r1 is an -Li"'-R3r1 group; 30 R3"1 is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2, 3, 4, or 5 optional substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is a Cl-C6 alkyl or phenyl; WO 2012/013728 PCT/EP2011/062949 42 L11"is chosen from a bond, - OCH 2 -, or -CH 2 0-; R21" is -Cyclopropyl-NH-L 2 r 1 -R4"' wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A"') and -NH 5 L 2 11 -R4"' are covalently attached; R41r is a 5-membered heteroaryl ring having 1, 2, or 3 optional substituents independently chosen from -NH 2 or -NH(Cl-C3) alkyl; 10 L 2 "' is -CH 2 - or -CH 2
CH
2 -; and wherein said compound of Formula (III) is optically active. Preferably, the optically active compound of Formula (III) is as follows: 15 Rl"-(A"')-R2"' (III) wherein: 20 (A"') is a phenyl or pyridyl group having 2 substituents, R I"' and R2"'; Rl"' is an -L1"'-R3"1 group; 25 R31 is a phenyl having 0, 1, 2, or 3 substituents independently chosen from -F, -Cl, -OH, NHSO 2 RA, Cl-C3 alkyl, Cl-C3 alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is Cl-C6 alkyl or phenyl; L "' is chosen from a bond, - OCH 2 -, or -CH 2 0-; 30 R21 is -Cyclopropyl-NH-L 2 "'-R4"1 wherein said cyclopropyl group has two chiral centers corresponding to the carbons to which (A"') and -NH-L 2 "'-R4"1 are covalently attached; WO 2012/013728 PCT/EP2011/062949 43 R4 is a 5-membered heteroaryl ring wherein said the chain of atoms comprising said 5 membered heteroaryl ring has 2 or 3 hetero atoms independently chosen from N, S, or 0, wherein said 5 membered heteroaryl has 1 optional substituent wherein said optional substituent is -NH 2 or -NH(Cl-C3) alkyl; 5
L
2 1 " is -CH 2 - or -CH 2
CH
2 -; or a pharmaceutically acceptable salt or solvate thereof, 10 and wherein said compound of Formula (III) is optically active. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 15 carrier. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 20 carrier, for use in treating or preventing a disease or disorder. Even more preferably, the optically active compound of Formula (III) is as follows: RI"I -(A"')-R2"' 25 (III) wherein: (A"') is a phenyl or pyridyl group having 2 substituents, RI' and R2"'; 30 R11r is an -L 1 n-R31' group; WO 2012/013728 PCT/EP2011/062949 44 R31 is a phenyl having 1, 2, or 3 optional substituents independently chosen from -F, -Cl, OH, -NHSO 2 CH3, methyl, methoxy, cyano, -CF 3 , or -OCF 3 ; Lill' is chosen from a bond, - OCH 2 -, or -CH 2 0-; 5 R2"r is -Cyclopropyl-NH-L 2 1 -R4." wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A") and -NH L21r-R4.. are covalently attached; 10 R4"' is an oxadiazolyl, thiadiazolyl, or thiazolyl ring having 1 optional substituent wherein said optional substituent is -NH 2 or -NH(C 1 -C3) alkyl;
L
2 1 " is -CH 2 - or -CH 2
CH
2 -; 15 or a pharmaceutically acceptable salt or solvate thereof, and wherein said compound of Formula (III) is optically active. The invention is also is a pharmaceutical composition comprising an optically active N 20 substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The invention is also is a pharmaceutical composition comprising an optically active N 25 substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or disorder. Preferably, the optically active compound of Formula (III) is as follows: 30 RI -(Ar1)-R2r1
(III)
WO 2012/013728 PCT/EP2011/062949 45 wherein:
(A
1 ) is a phenyl or pyridyl group having 2 substituents, RIl and R2... 5 Rl 1 is an -Li 1
-R
3 11 group; R3"1 is a phenyl having 0, 1, 2, or 3 substituents independently chosen from -F, -Cl, -OH, NHSO 2 RA, Cl-C3 alkyl, Cl-C3 alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is Cl-C6 alkyl or phenyl; 10 L1"' is chosen from a bond, - OCH 2 -, or -CH 2 0-; R21" is -Cyclopropyl-NH-L 2 11 1 -R4"' wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A"') and -NH 15 L 2
"
1 -R4"' are covalently attached; R41" is a 5-membered heteroaryl ring wherein said the chain of atoms comprising said 5 membered heteroaryl ring has 2 or 3 hetero atoms independently chosen from N, S, or 0, having 1 optional substituent wherein said optional substituent is -NH 2 or -NH(C1-C3) 20 alkyl;
L
2 '"'is -CH 2 - or -CH 2
CH
2 -; or a pharmaceutically acceptable salt or solvate thereof, 25 and wherein said compound of Formula (III) is optically active. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl-cyclopropylamine of Formula (III) as defined above, or 30 pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
WO 2012/013728 PCT/EP2011/062949 46 The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl-cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, for use in treating or preventing a disease or disorder. 5 Even more preferably, the optically active compound of Formula (III) is as follows: Rl"'(A1)-R21I (III) 10 wherein: (A"') is a phenyl or pyridyl group having 2 substituents, R111 and R2"; 15 R1" is an -L,"'-R3"' group; R3"1 is a phenyl having 0, 1, 2, or 3 substituents independently chosen from -F, -Cl, -OH, NHSO 2 CH3, methyl, methoxy, cyano, -CF 3 , or -OCF 3 ; 20 L11r is chosen from a bond, -OCH 2 -, or -CH 2 0-; R21r is -Cyclopropyl-NH-L 2 1 11 -R4"1 wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A"') and -NH L21r-R41" are covalently attached; 25 R41" is a heteroaryl group which is amide isostere having 1 optional substituent wherein said optional substituent is -NH 2 or -NH(C 1 -C3) alkyl;
L
2 " is -CH 2 - or -CH 2
CH
2 -; 30 or a pharmaceutically acceptable salt or solvate thereof, and wherein said compound of Formula (III) is optically active.
WO 2012/013728 PCT/EP2011/062949 47 The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 5 carrier. The invention is also is a pharmaceutical composition comprising an optically active N substituted aryl- or heteroaryl cyclopropylamine of Formula (III) as defined above, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable 10 carrier, for use in treating or preventing a disease or disorder. In one aspect, the invention is an optically active N-substituted aryl- or heteroaryl cyclopropylamine for use in a method of treating or preventing a disease or disorder. In a specific aspect, the disease or disorder is a human disease or disorder chosen from cancer, 15 depression, a neurodegenerative disease or condition, or a viral infection. In one aspect, the neurodegenerative disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In a specific aspect, the optically active N-substituted aryl- or heteroaryl cyclopropylamine is as defined in Formula (II) or (III). 20 The invention, in one aspect, is a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine (e.g., a compound of Formula (II) or (III) as described herein) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating or preventing a disease or disorder. In a related aspect, the method comprises administering to 25 an individual a therapeutically effective amount of a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine. Desirably, the disease or disorder is one that is treatable or preventable by LSD1 inhibition, LSD1 inhibition and MAO-B inhibition, or MAO-B inhibition. In a specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or 30 heteroaryl- cyclopropylamine which is 90% or greater (-) stereoisomer and 10% or less (+) stereoisomer. In a more specific aspect, a substantially pure stereoisomer of an N substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 95% or greater (-) stereoisomer and 5% or less (+) WO 2012/013728 PCT/EP2011/062949 48 stereoisomer. In yet a more specific aspect, a substantially pure stereoisomer of an N substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 98% or greater (-) stereoisomer and 2% or less (+) stereoisomer. In an even more specific aspect, a substantially pure stereoisomer of an N 5 substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 99% or greater (-) stereoisomer and 1% or less (+) stereoisomer. In yet an even more specific aspect, a substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine refers to an N-substituted aryl- or heteroaryl- cyclopropylamine which is 99.5% or greater (-) stereoisomer and 0.5% or less 10 (+)stereoisomer. In one embodiment, the above-described percentages refer to mole-%. The substantially pure stereoisomer of an N-substituted aryl- or heteroaryl- cyclopropylamine of this aspect is useful in treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection. In a specific aspect, the optically active N substituted aryl- or heteroaryl- cyclopropylamine is as defined in Formula (II) or (III). 15 Furthermore, in another aspect, the invention is a composition comprising a stereoisomer of an N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III) as described herein), or a pharmaceutically acceptable salt or solvate thereof, wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the N 20 substituted aryl- or heteroaryl- cyclopropylamine. In a specific aspect said composition has a 95% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. In a more specific aspect said composition has a 98% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl cyclopropylamine. In an even more specific aspect said composition has a 99% or more 25 enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl cyclopropylamine. The composition, in one aspect, is for use in treating or preventing cancer, depression, or a neurodegenerative disease or disorder, or a viral infection. In a specific aspect, the optically active N-substituted aryl- or heteroaryl- cyclopropylamine is as defined in Formula (II) or (III). 30 Furthermore, in another aspect, the invention is a pharmaceutical composition comprising a stereoisomer of an N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III) as described herein), or a pharmaceutically acceptable salt or solvate WO 2012/013728 PCT/EP2011/062949 49 thereof, and a pharmaceutically acceptable carrier wherein said composition has a 90% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl cyclopropylamine. In a specific aspect said composition has a 95% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. In 5 a specific aspect said composition has a 99% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl- or heteroaryl- cyclopropylamine. The pharmaceutical composition of this aspect is useful in treating or preventing cancer, depression, a neurodegenerative disease or disorder, or a viral infection. In a specific aspect, the optically active N-substituted aryl- or heteroaryl- cyclopropylamine is as defined 10 in Formula (II) or (III). In one aspect, the invention is a composition as defined herein comprising an optically active N-substituted aryl- or heteroaryl- cyclopropylamine of Formula (II) or (III), as described in any one of the above embodiments or aspects, or a solvate or a 15 pharmaceutically acceptable salt thereof, wherein said N-substituted aryl- or heteroaryl cyclopropylamine is the (IR, 2S) enantiomer (in respect to the substituents on the cyclopropyl ring) substantially free of the (1 S, 2R) enantiomer. Preferably, the N-substituted aryl- or heteroaryl- cyclopropylamine is more than 90% (1R, 2S) enantiomer and less than 10% (IS, 2R) enantiomer. More preferably, the N-substituted aryl- or heteroaryl 20 cyclopropylamine is more than 95% (IR, 2S) enantiomer and less than 5% (lS, 2R) enantiomer. Yet more preferably, the N-substituted aryl- or heteroaryl- cyclopropylamine is more than 98% (IR, 2S) enantiomer and less than 2% (1S, 2R) enantiomer. Even yet more preferably, the N-substituted aryl- or heteroaryl- cyclopropylamine is more than 99% (IR, 2S) enantiomer and less than 1% (1S, 2R) enantiomer. Still even more preferably, the N 25 substituted aryl- or heteroaryl- cyclopropylamine is more than 99.5% (IR, 2S) enantiomer and less than 0.5% (IS, 2R) enantiomer. The enantiomeric content can be determined, for example, by chiral HPLC e.g., (as described in Example 36). In one aspect, the invention is a composition as defined herein comprising an optically 30 active N-substituted aryl- or heteroaryl- cyclopropylamine of Formula (II) or (III), as described in any one of the above embodiments or aspects, or a solvate or a pharmaceutically acceptable salt thereof, wherein said N-substituted aryl- or heteroaryl cyclopropylamine is the (lS, 2R) enantiomer (in respect to the substituents on the WO 2012/013728 PCT/EP2011/062949 50 cyclopropyl ring) substantially free of the (IR, 2S) enantiomer. Preferably, the N substituted aryl- or heteroaryl- cyclopropylamine is more than 90% (1 S, 2R) enantiomer and less than 10% (1R, 2S) enantiomer. More preferably, the N-substituted aryl- or heteroaryl cyclopropylamine is more than 95% (IS, 2R) enantiomer and less than 5% (IR, 2S) 5 enantiomer. Yet more preferably, the N-substituted aryl- or heteroaryl- cyclopropylamine is more than 9 8 % (1S, 2R) enantiomer and less than 2 % (IR, 2S) enantiomer. Even yet more preferably, the N-substituted aryl- or heteroaryl- cyclopropylamine is more than 99% (IS, 2R) enantiomer and less than 1% (IR, 2S) enantiomer. Still even more preferably, the N substituted aryl- or heteroaryl- cyclopropylamine is more than 99.5% (IS, 2R) enantiomer 10 and less than 0.5% (iR, 2S) enantiomer. The enantiomeric content can be determined, for example, by chiral HPLC e.g., (as described in Example 36). In one aspect, the invention is an optically active N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (1I) or (III)), as defined in any one of the 15 above embodiments or aspects, or a solvate or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl ring carbon atom which is bound to the amino group of the N-substituted aryl- or heteroaryl- cyclopropylamine has the (S)-absolute configuration and the cyclopropyl ring carbon atom which is bound to the cyclic group adjacent to the cyclopropyl ring of the N-substituted aryl- or heteroaryl- cyclopropylamine has the (R) 20 absolute configuration. Preferably, said N-substituted aryl- or heteroaryl- cyclopropylamine is provided in an enantiomeric excess of at least 90%. Even more preferably said N substituted aryl- or heteroaryl- cyclopropylamine is provided in an enantiomeric excess of at least 95%. Yet still more preferably said compound is provided in an enantiomeric excess of at least 98%. Still more preferably said N-substituted aryl- or heteroaryl- cyclopropylamine 25 is provided in an enantiomeric excess of at least 99%. The enantiomeric excess can be determined, for example, by chiral HPLC e.g., (as described in Example 36). In one aspect, the invention provides an optically active N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III)), as defined in any one of the 30 the above embodiments or aspects, or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl ring carbon atom which is bound to the amino group of the compound has the (R) absolute configuration and the cyclopropyl ring carbon atom which is bound to the cyclic group adjacent to the cyclopropyl ring of the compound has the (S) WO 2012/013728 PCT/EP2011/062949 51 absolute configuration. Preferably, said compound is provided in an enantiomeric excess of at least 90%. Even more preferably said compound is provided in an enantiomeric excess of at least 95%. Yet still more preferably said compound is provided in an enantiomeric excess of at least 98%. Still more preferably said compound is provided in an enantiomeric 5 excess of at least 99%. The enantiomeric excess can be determined, for example, by chiral HPLC e.g., (as described in Example 36). In one aspect, the invention is an optically active N-substituted aryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III) as described herein), or a 10 pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a disease or disorder. In a related aspect, the method comprises administering to an individual in need of treatment a therapeutically effective amount of an optically active N-substituted aryl- or heteroaryl-cyclopropylamine or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the disease or disorder is a human disease or disorder chosen from 15 cancer, a neurological disease or condition, or a viral infection. In one aspect, the neurological disease or disorder is depression, Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In one specific aspect, the cancer is prostate cancer. In another specific, the cancer is breast cancer. In another aspect, the cancer is lung cancer. In another aspect, 20 the cancer is colorectal cancer. In another specific aspect, the cancer is brain cancer. In another specific aspect, the cancer is skin cancer. In another specific aspect, the cancer is blood cancer (e.g., a leukemia (including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia 25 (ALL), or hairy cell leukemia) or a lymphoma). In another specific aspect, the cancer is a myeloma. In one aspect, the neurological disease or condition is depression, Huntington disease, Parkinson disease, or Alzheimer disease. In one aspect, the viral infection is HSV1 or HSV2. In one aspect, the disease or condition is depression. In one aspect, the neurological disease or condition is a neurodegenerative disease or condition. In one aspect, 30 the neurodegenerative disease or disorder is Huntington disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia. In one aspect, the neurodegenerative disease or disorder is Huntington disease. In one aspect, the neurodegenerative disease or disorder is Parkinson disease. In one aspect, the WO 2012/013728 PCT/EP2011/062949 52 neurodegenerative disease or disorder is Alzheimer disease. In one aspect, the neurodegenerative disease or disorder is Amyotrophic Lateral Sclerosis. In one aspect, the neurodegenerative disease or disorder is Frontotemporal Dementia. 5 The invention further relates to the optically active N-substituted aryl- or heteroaryl cyclopropylamine of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, as defined in the above embodiments or aspects, for use in the treatment or prevention of a disease or disorder, in particular cancer (e.g., breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia 10 (including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma, or myeloma), a neurological disease or condition (e.g., depression, Alzheimer's disease, Huntington disease, Parkinson's disease, or Dementia with Lewy Bodies), or a viral 15 infection (e.g., a viral infection is caused by and/or associated with HIV, or a herpesvirus infection, such as a herpesvirus infection caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, or Epstein-Barr virus) in a subject (preferably a mammal, more preferably a human). 20 The invention further relates to the optically active N-substituted aryl- or heteroaryl cyclopropylamine of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, as defined in anyone of the above embodiment, for use in the treatment or prevention of a disease or disorder wherein said disease or disorder is a neurodegenerative disease or disorder. In one aspect, the neurodegenerative disease or disorder is Huntington 25 disease, Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, or Frontotemporal Dementia. In one embodiment the invention provides a compound Formula (I), (Ia) or (Tb) or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is: 30 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin -2-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine; WO 2012/013728 PCT/EP2011/062949 53 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol 2-amine; 5 3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methvlamino)cyclopropyl)pyridin-2-yl)phenol; 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine; 10 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; 5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 15 5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5 -((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 20 2-amine; 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol 2-amine; 25 N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; 4'-((trans)-2-(((5 -amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1 '-biphenyl]-3 ol; 5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)- 1,3,4 30 oxadiazol-2-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine; WO 2012/013728 PCT/EP2011/062949 54 4-((((trans)-2-(3'-(trifluoromethyl)-[1,1 '-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol 2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine; 5 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine; 10 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine; or 3 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-triazin-6-amine;. 15 In one embodiment of the invention provides a pharmaceutical composition comprising a pharmaceutically carrier and a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin -2-amine; 20 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol 2-amine; 25 3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine; 30 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; 5 -((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine; WO 2012/013728 PCT/EP2011/062949 55 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine; 5 -((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5 5 -((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 10 2-amine; 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl- 1,3,4-oxadiazol 2-amine; N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; 15 4'-((trans)-2-(((5 -amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[ 1,1 '-biphenyl]-3 ol; 5 -((((trans)-2-(6-(3 -(trifluoromethyl)phenyl)pyridin-3 -yl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine; 20 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine; 4-((((trans)-2-(3'-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol 2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine; 3 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine; 25 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methy)pyridazin-3-amine; 30 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine; or 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine; WO 2012/013728 PCT/EP2011/062949 56 In one embodiment of the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof. wherein said compound is: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin 5 -2-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol 10 2-amine; 3 -(5 -((trans)-2-((2-aminopyrimidin-5 -yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 15 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,2,4-oxadiazol-3-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; 5 -((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5 -((((trans)-2-(4-((3 -fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 20 2-amine; 5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 25 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol 30 2-amine; N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; WO 2012/013728 PCT/EP2011/062949 57 4'-((trans)-2-(((5-amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1 '-biphenyl]-3 ol; 5-((((trans)-2-(6-(3 -(trifluoromethyl)phenyl)pyridin-3 -yl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine; 4-((((trans)-2-(3'-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol 2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine; 10 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine; 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-oxadiazol-3-amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine; 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-thiadiazol-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine; 15 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine; or 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine; 20 for use in a method of treating or preventing a neurological disease or condition. In one aspect, the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. 25 In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin -2-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine; 30 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol 2-amine; WO 2012/013728 PCT/EP2011/062949 58 3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 5 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,2,4-oxadiazol-3-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; 5 -((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5 -((((trans)-2-(4-((3 -fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 10 2-amine; 5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 15 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine; 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl- 1,3,4-oxadiazol 20 2-amine; N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; 4'-((trans)-2-(((5 -amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1 -biphenyl] -3 ol; 25 5 -((((trans)-2-(6-(3 -(trifluoromethyl)phenyl)pyridin-3 -yl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-amine; 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-thiadiazol-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazo-5-amine; 4-((((trans)-2-(3'-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol 30 2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-oxadiazol-3-amine; WO 2012/013728 PCT/EP2011/062949 59 3 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-oxadiazol-5 -amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4-thiadiazol-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine; 5 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine; or 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine; for use in a method of treating or preventing cancer. In one aspect, the cancer is chosen 10 from prostate, testicular, brain, colorectal, lung, breast, lymphoma, skin, or blood cancer. In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is: 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 15 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; 5 -((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine; or 5 -((((trans)-2-(4-((3 -fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 20 2-amine; for use in a method of treating or preventing a neurological disease or condition. In one aspect, the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. 25 In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol, for use in a method of treating or preventing a neurological disease or condition. In one 30 aspect, the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.
WO 2012/013728 PCT/EP2011/062949 60 In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine, for use in a method of treating or preventing a neurological disease or condition. In one aspect, 5 the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically 10 acceptable salt thereof, wherein said compound is 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine, for use in a method of treating or preventing a neurological disease or condition. In one aspect, the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia 15 with Lewy Bodies. In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof wherein said compound is 5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 20 2-amine, for use in a method of treating or preventing a neurological disease or condition. In one aspect, the neurological disease or condition is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies. 25 In one embodiment the invention relates to a compound, or a solvate or a pharmaceutically acceptable salt thereof, wherein said compound is 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine, for use in a method of treating or preventing a neurological disease or condition. In one aspect, the neurological disease or condition is chosen from Alzheimer Disease, 30 Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.
WO 2012/013728 PCT/EP2011/062949 61 In one embodiment of the invention provides an optically active N-substituted aryl- or heteroaryl cyclopropylamine or a pharmaceutically acceptable salt or solvate thereof, wherein said optically active N-substituted aryl- or heteroaryl- cyclopropylamine is chosen from 5 (-) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; (-) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 10 yl)acetamide; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2 amine; or (-) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 15 oxadiazol-2-amine. In a related aspect, the invention relates to a compound selected from: (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine; (-) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 20 oxadiazol-2-amine; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; (-) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; 25 (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-thiadiazol-2 amine; (-) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; or 30 a pharmaceutically acceptable salt or solvate thereof; for use in a method of treating or preventing a neurological disease or condition (e.g., depression). Preferably, the neurological disease or condition is chosen from depression, WO 2012/013728 PCT/EP2011/062949 62 Alzheimer disease, Huntington disease, Parkinson disease, Frontotemporal Dementia, Dementia with Lewy Bodies, or Amyotrophic Lateral Sclerosis. The invention thus is a compound or composition having an optically active N-substituted 5 aryl- or heteroaryl- cyclopropylamine. Preferably, the optically active N-substituted aryl- or heteroaryl-cyclopropylamine is as defined herein in any one of the embodiments or aspects of Formula (II) or (III). More preferably, the optically active N-substituted aryl- or heteroaryl-cyclopropylamine has a kinact/KI value for LSD1 which is at least 50 fold higher than the kinact/KI value for MAO-A. Still more preferably, the kinact/Ki value for 10 LSD 1 is at least 100-fold higher than kinact/KI for MAO-A. Even more preferably, the LSD1 kinact/KI value is at least 250-fold higher than the kinact/KI value for MAO-A. Yet even more preferably, the LSD1 kinact/KI value is at least 500-fold higher than the kinact/KI value for MAO-A. 15 Preferably, the optically active N-substituted aryl- or heteroaryl- cyclopropylamine is as defined herein in any one of the embodiments or aspects of Formula (II) or (III). More preferably, the optically active N-substituted aryl- or heteroaryl-cyclopropylamine has kinact/KI value for LSDl and MAO-B which are at least 50-fold higher than the kinact/Ki value for MAO-A. Preferably, the kinact/KI value for LSD 1 and MAO-B are at least 100 20 fold higher than kinact/KI for MAO-A. Even more preferably, the LSD1 and MAO-B kinact/KI values are at least 250-fold higher than the kinact/KI value for MAO-A. Yet even more preferably, the LSD1 and MAO-B kinact/KI values are at least 500-fold higher than the kinact/KI value for MAO-A. 25 Preferably, the optically active N-substituted aryl- or heteroaryl-cyclopropylamine is as defined herein in any of the embodiments of Formula (I) or (II). More preferably, the optically active N-substituted aryl- or heteroaryl-cyclopropylamine has a kinact/KI value for MAO-B which is at least 50-fold higher than the kinact/KI value for MAO-A. Preferably, the kinact/KI value for MAO-B is at least 100-fold higher than kinact/KI for MAO-A. Even 30 more preferably, the MAO-B kinact/KI value is at least 500-fold higher than the kinact/KI value for MAO-A. Yet even more preferably, the MAO-B kinact/KI is at least 1000-fold higher than the kinact/KI value for MAO-A. Yet even still more preferably, the MAO-B kinact/KI value is at least 2000-fold higher than the kinact/KI value for MAO-A.
WO 2012/013728 PCT/EP2011/062949 63 The optically active N-substituted aryl- or heteroaryl-cyclopropylamine, pharmaceutical composition comprising the optically active N-substituted aryl- or heteroaryl cyclopropylamine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically 5 acceptable carrier, and methods of their use have unexpected selectivity for LSD1 and/or MAOB. The (-) stereoisomers of N-substituted aryl- or heteroaryl-cyclopropylamines (e.g., of the compounds of Formula (II) or (III) as described herein) are unexpectedly potent and selective inhibitors of LSD 1 and/or MAO-B. Avoiding inhibition of "off-targets" can avoid unwanted or undesirable side-effects like the cheese effect associated with MAO-A. 10 The optically active compounds of the invention can be prepared by chiral HPLC from e.g., racemates, chiral synthesis with compounds of known chirality, or chiral recrystallization using chiral salts. 15 In one aspect, the invention provides a method for enriching an enantiomer of a trans N substituted cyclopropylamine (e.g., an enantiomer of a compound of Formula (II) or (III) or an enantiomer of a compound of Formula (I), wherein the substituents on the cyclopropyl moiety comprised in Formula (I) (i.e., the substituent (A) and the substituent -NH-CH 2 -(D)) are in trans-configuration, the method comprising: contacting a trans-substituted 20 cyclopropylamine with a chiral recrystallization agent in a solvent (particularly under conditions that are sufficient for the crystallization of the salt of the chiral recrystallization agent and the trans substituted cylopropylamine); and isolating the crystallized salt of the chiral recrystallization agent and the trans substituted cyclopropylamine. In another preferred aspect, the trans cyclopropylamine is trans 4-benzoxy-2-phenylcyclopropylamine 25 or a protected derivative thereof. In a preferred aspect, the trans N-substituted cyclopropylamine is of Formula (II) or (III) as described above or a derivative thereof wherein the -L2 1 1 -R4r group or the the -L2 1 1 1 -R4" 1 group is absent or substituted with a protecting group. In a preferred aspect, the chiral recrystallization agent is chosen from S (+) mandelic acid, D (-) tartaric acid, L (-) di-p-toluoyl tartaric acid, or R (-) mandelic acid. 30 In one preferred aspect, the chiral recrystallization agent is R (-) mandelic acid. In one aspect, the solvent is THF and H 2 0.
WO 2012/013728 PCT/EP2011/062949 64 In one aspect, the invention provides a method for preparing an enantiomer of a trans N substituted cyclopropylamine comprising: contacting a trans-substituted cyclopropylamine with a chiral recrystallization agent in a solvent (particularly under conditions are sufficient for the crystallization for the salt of the chiral recrystallization agent and the trans 5 substituted cyclopropylamine); and isolating the crystallized salt of the chiral recrystallization agent and the trans substituted cyclopropylamine, thereby preparing an enatiomer of a trans N-substituted cyclopropylamine. In a preferred aspect, the trans N substituted cyclopropylamine is of Formula (II) or (III) as defined above or a derivative thereof wherein the -L2"-R4" group or the the -L2"'-R4"' group is absent or substituted with 10 a protecting group. In another preferred aspect, the trans cyclopropylamine is trans 4 benzoxy-2-phenylcyclopropylamine or a protected derivative thereof. In a preferred aspect, the chiral recrystallization agent is chosen from S (+) mandelic acid, D (-) tartaric acid, L ( ) di-p-toluoyl tartaric acid, or R (-) mandelic acid. In one preferred aspect, the chiral recrystallization agent is R (-) mandelic acid. In one aspect, the solvent is THF and H 2 0. 15 Additionally, the invention relates to the (+) enantiomer of a trans N-substituted aryl- or heteroaryl-cyclopropylamine, including the compounds of Formula (II) or (III) and the compounds of Formula (I), in which the substituents on the cyclopropylamine moiety are in trans-orientation. For example, a corresponding optically active (+) enantiomer may be 20 selected from: (+) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; (+) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; 25 (+) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 yl)acetamide; (+) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine; (+) 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-thiadiazol-2 amine; 30 (+) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof. The present invention furthermore relates to the following items: WO 2012/013728 PCT/EP2011/062949 65 1. An optically active N-substituted aryl- or heteroaryl-cyclopropylamine or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating or preventing a disease. 5 2. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of item 1 wherein said N-substituted aryl- or heteroaryl cyclopropylamine is a trans N substituted aryl- or heteroaryl cyclopropylamine that rotates plane polarized light in the (-) sense or is the (-) stereoisomer. 3. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of item 1 or 10 2 wherein said N-substituted aryl- or heteroaryl cyclopropylamine is 90% or greater (-) stereoisomer and 10% or less (+) steroisomer. 4. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of item 1 or 2 wherein said N-substituted aryl- or heteroary.1 cyclopropylamine is 95% or greater (-) stereoisomer and 5% or less (+). 15 5. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of item 1 or 2 wherein said N-substituted aryl- or heteroaryl. cyclopropylamine is 98% or greater (-) stereoisomer and 2% or less (+). 6. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of item 1 or 2 wherein said N-substituted aryl- or heteroaryl cyclopropylamine is 99% or greater 20 (-) stereoisomer and 1% or less (+). 7. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of item 1 or 2 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine is 99.5% or greater (-) stereoisomer and 0.5% or less (+). 8. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of item 1 or 25 2 having a 90% or more enantiomeric excess of the (-) stereoisomer of the N substituted aryl- or heteroaryl- cyclopropylamine. 9. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of item 1 or 2 having a 95% or more enantiomeric excess of the (-) stereoisomer of the N substituted aryl- or heteroaryl- cyclopropylamine. 30 10. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 1 or 2 having a 98% or more enantiomeric excess of the (-) stereoisomer of the N substituted aryl- or heteroaryl- cyclopropylamine.
WO 2012/013728 PCT/EP2011/062949 66 11. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 1 or 2 having a 99% or more enantiomeric excess of the (-) stereoisomer of the N substituted aryl- or heteroaryl- cyclopropylamine. 12. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any of of 5 items 1-11, or a pharmaceutically acceptable salt thereof, wherein said N-substituted aryl- or heteroaryl cyclopropylamine is of Formula (II): Rllr-(A"l)-R21 10 wherein (A") is an aryl or heteroaryl group having 2 substituents, RI" and R2", and 1 to 3 optional substituents wherein said optional substituents are independently chosen from halo, C1-C3 alkyl, or C1-C3 alkoxy; R1" is an -L1-R3 group; R3" is a aryl or heteroaryl group having 1, 2, 3, 4, or 5 optional substituents 15 independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or
-OCF
3 wherein RA is a C1-C6 alkyl or phenyl; Lil is chosen from a bond, -CH 2 0-, -CH 2
CH
2 0-, -O CH 2 -, -OCH 2
CH
2 -, -CH 2 -,
-CH
2
CH
2 -, -CH 2
CH
2
CH
2 -, or -0-. R2" is -Cyclopropyl-NH-L 2 r-R4" wherein said cyclopropyl group has two chiral 20 centers substituted in the trans orientation corresponding to the carbons to which (A") and -NH-L 2 r-R4" are covalently attached; R4" is a 5 or 6 membered heteroaryl ring having 1, 2, or 3 optional substituents wherein said optional substituents are independently chosen from alkyl, NHRB OR B, or halo wherein RB is a hydrogen, C1-C3 alkyl, or -C(=O)CH 3 ; 25 L 2 1 ' is a branched or unbranched C1 -C4 alkylene group. 13. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of item 12 wherein (A") is an aryl or heteroaryl group having 2 substituents, RI" and R2", and 1, 2, or 3 optional substituents wherein said optional substituents are independently chosen from halo, Cl-C3 alkyl, or C1-C3 alkoxy. 30 14. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 12 wherein R3" is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2, or 3 optional substituents independently chosen from halo, -OH, -NHSO 2 RA, alkyl, alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is C1-C6 alkyl or phenyl.
WO 2012/013728 PCT/EP2011/062949 67 15. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 12 wherein L 1 1 is chosen from a bond, - OCH 2 -, or -CH 2 0-. 16. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 12 wherein R4 1 ' is a 5-membered heteroaryl ring having 1, 2, or 3 optional substituents 5 independently chosen from -NH 2 or -NH(C 1 -C3) alkyl. 17. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 12 wherein L 2 1 is -CH 2 - or -CH 2
CH
2 -. 18. The use of any one of items 1-17 wherein said method of treating or preventing is a method of treating or preventing cancer, depression, a neurodegenerative disease or 10 disorder, or a viral infection. 19. The use of item 17 wherein said neurodegenerative disease or disorder is chosen from Alzheimer Disease, Parkinson Disease, Huntington Disease, Frontotemporal Dementia or Amytrophic Lateral Sclerosis. 20. The use of item 17 wherein said neurodegenerative disease or disorder is chosen 15 from Alzheimer Disease, Parkinson Disease, Huntington Disease, Frontotemporal Dementia or Amytrophic Lateral Sclerosis. 21. The use of item 17 wherein said neurodegenerative disease or disorder is Alzheimer Disease. 22. The use of item 17 wherein said neurodegenerative disease or disorder is Parkinson 20 Disease. 23. The use of item 17 wherein said neurodegenerative disease or disorder is Huntington Disease. 24. The use of item 17 wherein said neurodegenerative disease or disorder is Frontotemporal Dementia. 25 25. The use of item 17 wherein said neurodegenerative disease or disorder is Amytrophic Lateral Sclerosis. 26. An optically active compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (III): R11r-(Ar1)-R2"1 30 wherein (A"') is an aryl or heteroaryl group having 2 substituents, RI"' and R2"', and 1 to 3 optional substituents wherein said optional substituents are independently chosen from halo, C1-C3 alkyl, or Cl-C3 alkoxy; WO 2012/013728 PCT/EP2011/062949 68 RIm is an -Lim 1 -R3m' group; R3m1 is a phenyl, pyridyl, thiazolyl, or thienyl group having 0, 1, 2, or 3 substituents independently chosen from -F, -Cl, -OH, -NHSO 2 RA, C1-C3 alkyl, C1-C3 alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is C1-C6 alkyl or phenyl; 5 Li1 is chosen from a bond, -CH 2 0-, or -CH 2 0-, R2"1 is -Cyclopropyl-NH-L 2 m 1 -R4" wherein said cyclopropyl group has two chiral centers substituted in the trans orientation corresponding to the carbons to which (A"') and -NH-L 2 1 1 1 -R4m' are covalently attached; R4m' is a 5-membered heteroaryl ring having 1, 2, or 3 optional substituents wherein 10 said optional substituents are independently chosen from -NH 2 or -NH(C1-C3) alkyl; and
L
2 . is -CH 2 - or -CH 2
CH
2 -. 27. The compound of item 26 wherein (A") is a phenyl or pyridyl group. 28. The compound of item 26 wherein R3m' is a phenyl having 0, 1, 2, or 3 substituents 15 independently chosen from -F, -Cl, -OH, -NHSO 2 R , Cl-C3 alkyl, Cl-C3 alkoxy, cyano, -CF 3 , or -OCF 3 wherein RA is C1-C6 alkyl or phenyl; 29. The compound of item 26 wherein Lim is chosen from a bond, -OCH 2 -, or -CH 2 0-, 30. The compound of item 26 wherein R4m' is a 5-membered heteroaryl ring wherein the chain of atoms comprising said 5-membered heteroaryl ring has 2 or 3 hetero atoms 20 independently chosen from N, S, or 0 and said heteroaryl ring has 1 optional substituent wherein said optional substituent, if present, is -NH 2 or -NH(C1-C3) alkyl. 31. The compound of item 26 wherein L 2 ' is -CH 2 - or -CH 2
CH
2 -. 32. The compound of item 26 wherein R3m11 is a phenyl having 0, 1, 2, or 3 substituents 25 independently chosen from -F, -Cl, -OH, -NHSO 2
CH
3 , methyl, methoxy, cyano, CF 3 , or -OCF 3 . 33. The compound of item 26 wherein R4m' is an oxadiazolyl, thiadiazolyl, or thiazolyl ring having 1 optional substituent wherein said optional substituent, if present, is
-NH
2 or -NH(C1-C3) alkyl. 30 34. The compound of item 26 wherein R4m' is an oxadiazolyl ring having 1 optional substituent chosen from -NH 2 or -NH(C1-C3) alkyl.
WO 2012/013728 PCT/EP2011/062949 69 35. The optically active N-substituted aryl- or heteroaryl-cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl cyclopropylamine rotates plane polarized light in the (-) sense or is the (-) enantiomer. 36. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any one 5 of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine is 90% or greater (-) stereoisomer and 10% or less (+) steroisomer. 37. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of item 1 any one of items 26-34 wherein said N-substituted aryl- or heteroaryl cyclopropylamine is 95% or greater (-) stereoisomer and 5% or less (+). 10 38. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl-cyclopropylamine 98% or greater (-) stereoisomer and 2% or less (+). 39. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl-cyclopropylamine 99% 15 or greater (-) stereoisomer and 1% or less (+). 40. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine 99.5% or greater (-) stereoisomer and 0.5% or less (+). 41. The optically active N-substituted aryl- or heteroaryl- cyclopropylamine of any one 20 of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine has a 90% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl or heteroaryl- cyclopropylamine. 42. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine has 25 a 95% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl or heteroaryl- cyclopropylamine. 43. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine has a 98% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl 30 or heteroaryl- cyclopropylamine. 44. The optically active N-substituted aryl- or heteroaryl cyclopropylamine of any one of items 26-34 wherein said N-substituted aryl- or heteroaryl- cyclopropylamine has WO 2012/013728 PCT/EP2011/062949 70 a 99% or more enantiomeric excess of the (-) stereoisomer of the N-substituted aryl or heteroaryl- cyclopropylamine. 45. A method of treatment or prevention of a disease or disorder said method comprising administering to an individual in need of said treatment or prevention an effective 5 amount of an optically active N-substituted aryl- or heteroaryl-cyclopropylamine or a pharmaceutically acceptable salt or solvate thereof. 46. The method of item 45 wherein said optically active N-substituted aryl- or heteroaryl-cyclopropylamine is as in any one of items 26-44. 47. The method of item 45 or 46 wherein said disease or disorder is chosen from cancer, 10 a neurodegenerative disease or disorder, viral infection, or depression. 48. The method of item 45 or 46 wherein said disease or disorder is a neurodegenerative disease or disorder chosen from Alzheimer disease, Parkinson disease, Huntington Disease, Frontotemporal Dementia, or Amytrophic Lateral Sclerosis. 49. A optically active compound or a pharmaceutically acceptable salt or solvate thereof 15 wherein said optically active compound is chosen from: (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol 2-amine; (-) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 20 (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; (-) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-yl)acetamide; (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2 25 amine; or (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol 2-amine. 50. The compound of item 49 chosen from (-) N-(5-(((2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide; (-) 30 5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol 2-amine; or (-) 5-(((2-(4-(benzyloxy)phenyl)cyclopropylanino)methyl)-1,3,4 oxadiazol-2-amine.
WO 2012/013728 PCT/EP2011/062949 71 51. The compound of item 49 which is (-) 5-(((2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl- 1,3,4-oxadiazol-2-amine. 52. The compound of item 49 which is (-) 5-(((2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine. 5 53. The compound of item 49 which is (-) N-(5-(((2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol-2-yl)acetamide. 54. A pharmaceutical composition comprising an optically active compound as in any one of items 26-44 or 49 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 10 55. The pharmaceutical composition of 54 for use in a method of treating or preventing a disease or disorder. 56. The pharmaceutical composition of item 55 wherein said disease or disorder is a human disease or disorder chosen from cancer, a neurological disease or disorder, or a viral infection. 15 57. The pharmaceutical composition of item 56 where n said neurological disease or disorder is depression or a neurodegenerative disease or disorder. 58. The pharmaceutical composition of item 57 wherein said neurodegenerative disease or disorder is Alzheimer disease, Parkinson disease, Huntington Disease, Frontotemporal Dementia, or Amytrophic Lateral Sclerosis. 20 59. An optically active compound chosen from: (+) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; (+) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; 25 (H) N-(5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 oxadiazol-2-yI)acetamide; (+) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2 amine; or 30 (H) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4 thiadiazol-2-amine; or a pharmaceutical acceptable salt or solvate thereof. 60. A method for enriching an enantiomer of a trans N-substituted cyclopropylamine comprising: contacting a trans-substituted cyclopropylamine with a chiral WO 2012/013728 PCT/EP2011/062949 72 recrystallization agent in a solvent and under conditions are sufficient for the crystallization for the salt of the chiral recrystallization agent and the trans substituted cylopropylamine; and isolating the crystallized salt of the chiral recrystallization agent and the trans substituted cyclopropylamine. 5 61. The method of item 60 wherein the trans cyclopropylamine is trans 4-benzoxy-2 phenylcyclopropylamine or a protected derivative thereof 62. The method of item 60 wherein the chiral recrystallization agent is chosen from S (+) mandelic acid, D (-) tartaric acid, L (-) di-p-tolyl tartaric acid, or R (-) mandelic acid. 10 63. The method of item 60 or 61 wherein the chiral recrystallization agent is R (-) mandelic acid. 64. The method of item 60, 61, 62, or 63 wherein the solvent is THF and H 2 0. Definitions: 15 Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the 20 term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. As used herein, the term "acyl," refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other moiety where the atom attached to the 25 carbonyl is carbon. An "acetyl" group refers to a -C(=O)CH 3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, alkanoyl or aroyl. 30 As used herein, the term "alkenyl," refers to a straight-chain or branched-chain hydrocarbon WO 2012/013728 PCT/EP2011/062949 73 group having one or more double bonds and containing from 2 to 20 carbon atoms. A (C2 C6)alkenyl has from 2 to 6 carbon atoms. As used herein, the term "alkoxy," refers to an alkyl ether group, wherein the term alkyl is 5 as defined below. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or n-pentoxy. As used herein, the term "alkyl," refers to a straight-chain or branched-chain alkyl group 10 containing from 1 to 20 carbon atoms. A (Cl-Cl 0)alkyl has from 1 to 10 carbon atoms and a (Cl-C6)alkyl has from 1 to 6 carbon atoms and a (Cl-C4)alkyl has from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl, octyl, or nonyl. 15 As used herein, the term "alkylene" refers to an alkyl group attached at two positions, i.e. an alkanediyl group. Examples include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, or nonylene. Accordingly, the term "alkylene" may, e.g., refer to a straight-chain or branched-chain alkylene group having from 20 1 to 6 carbon atoms. As used herein, the term "alkylamino," refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups including, but not limited to N-methylamino, N-ethylamino, 25 N,N-dimethylamino, N,N-ethylmethylamino, N,N-diethylamino, N-propylamino, and N,N methylpropylamino. As used herein, the term "alkynyl," refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. A (C2 30 C6)alkynyl has from 2 to 6 carbon atoms. A (C2-C4)alkynyl has from from 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn- 1 -yl, butyn-2-yl, pentyn- 1 -yl, 3-methylbutyn- 1 -yl, or hexyn-2-yl.
WO 2012/013728 PCT/EP2011/062949 74 As used herein, the terms "amido" and "carbamoyl," refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group (e.g., C(=O)NRR') , or vice versa (-N(R)C(=O)NR'). "Amido" and "carbamoyl" encompass "C 5 amido", "N-amido" and "acylamino" as defined herein. R and R' are as defined herein. As used herein, the term "C-amido," refers to a -C(=O)NRR' group with R and R' as defined herein. 10 As used herein, the term "amino," refers to--NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl, and heterocyclyl,. Additionally, R and R' may be combined to form a heterocyclyl. As used herein, the term "aryl," refers a carbocyclic aromatic system containing one ring, or 15 two or three rings fused together where in the ring atoms are all carbon. The term "aryl" groups includes, but is not limited to groups such as phenyl, naphthyl, or anthracenyl. As used herein, the term "arylalkoxy" or "aralkoxy," refers to an aryl group attached to the parent molecular moiety through an alkoxy group. Examples of arylalkoxy groups include, 20 but are not limited to, benzyloxy or phenethoxy. As used herein, the term "arylalkyl" or "aralkyl," refers to an aryl group attached to the parent molecular moiety through an alkyl group. As used herein, the term "aryloxy," refers to an aryl group attached to the parent molecular 25 moiety through an oxy (-0-). As used herein, the term "carbamate," refers to an O-carbamyl or N-carbamyl group as defined herein. 30 As used herein, the term "carbonyl," when alone includes formyl -C(=0)H and in combination is a -C(=0)- group. As used herein, the term "carboxyl" or "carboxy" refers to -C(=0)OH or the corresponding WO 2012/013728 PCT/EP2011/062949 75 "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(=O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(=O)OR groups where R is as defined herein. 5 As used herein, the term "cyano" refers to -CN. As used herein, the term "carbocyclyl" refers to a saturated or partially saturated monocyclic or a fused bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. 10 "Carbocyclyl" encompasses benzo fused to a carbocyclyl ring system. One group of carbocyclyls have from 5 to 7 carbon atoms. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro- 1 H-indenyl, or adamantyl. 15 As used herein, the term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. One group of cycloalkyls has from 5 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. 20 As used herein, the term "cycloalkenyl" refers to a partially saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. One group of carboalkenyls have from 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, but 25 are not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl. As used herein, the term "cyclyl" refers to an aryl, heterocyclyl, or carbocyclyl group as defined herein. 30 As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein, the term "haloalkoxy" refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. Examples of haloalkoxy groups include, but are WO 2012/013728 PCT/EP2011/062949 76 not limited to, trifluoromethoxy, 2-fluoroethoxy, or 3-chloropropoxy. As used herein, the term "haloalkyl" refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced 5 are monohaloalkyl, dihaloalkyl or polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo or polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 10 trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl or dichloropropyl. As used herein, the term "heteroalkyl" refers to a straight or branched alkyl chain, wherein one, two, or three carbons forming the alkyl chain are each replaced by a heteroatom 15 independently selected from the group consisting of 0, N, and S, and wherein the nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized. The heteroatom(s) 0, N and S may, for example, be placed at an interior position of the heteroalkyl group, i.e., the heteroalkyl may be bound to the remainder of the molecule via a carbon atom. Up to two 20 heteroatoms may be consecutive, such as, for example, -CH 2
-NH-OCH
3 . Accordingly, a further example for a "heteroalkyl" group is a straight or branched alkyl group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., -S(=0) 2
-NH
2 , -S(=O) 2 -NH(alkyl) or -S(=O) 2 -N(alkyl)(alkyl). 25 As used herein, the term "heteroalkylene" refers to a heteroalkyl group attached at two positions. Examples include, but are not limited to, -CH 2 0CH 2 -, -CH 2
SCH
2 -, and CH 2
NHCH
2 -, -CH 2 S-, or -CH 2
NHCH(CH
3
)CH
2 -. Accordingly, the term "heteroalkylene" may, e.g., refer to a straight or branched alkylene group (i.e., a straight or branched 30 alkanediyl group) having from 1 to 6 carbon atoms, wherein 1, 2 (if present) or 3 (if present) of said carbon atoms are each replaced by a heteroatom independently selected from 0, N or S. It is to be understood that the presence of hydrogen atoms will depend on the valence of the heteroatom replacing the respective carbon atom. If, for example, the carbon atom in a WO 2012/013728 PCT/EP2011/062949 77
-CH
2 - group is replaced by 0 or S, the resulting group will be -0- or -S-, respectively, while it will be -N(H)- when the carbon atom replaced by N. Likewise, if the central carbon atom in a group -CH 2
-CH(-CH
3
)-CH
2 - is replaced by N, the resulting group will be -CH 2 N(-CH 3
)-CH
2 -. An example for a "heteroalkylene" group is a straight or branched alkylene 5 group, in which two consecutive carbon atoms are replaced by the heteroatoms S and N, respectively, and the sulfur heteroatom is furthermore oxidized, resulting in moieties such as, e.g., -S(=O) 2 -N(H)- or -S(=0) 2 -N(alkyl)-. Accordingly, the groups -S(=0) 2 -N(H)- and
-S(=O)
2 -N(alkyl)- (e.g., -S(=0) 2
-N(C
1
-C
6 alkyl)-) are exemplary "heteroalkylene" groups. 10 As used herein, the term "heteroaryl," refers to a 3 to 7 membered unsaturated monocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which the rings are aromatic and which at least one ring contains at least one atom selected from the group consisting of 0, S, and N. One group of heteroaryls has from 5 to 7 carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, 15 pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, 20 quinoxalinyl, naphthyridinyl, or furopyridinyl. As used herein, the term "heterocyclyl" or "hetercycle," each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be 25 independently selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitron or sulfur atoms may be oxidized (e.g., -N=O, -S(=O)-, or -S(=0)2-). Additionally, 1, 2, or 3 of the carbon atoms of the heterocyclyl may be optionally oxidized (e.g., to give an oxo group or =0). One group of heterocyclyls has from 1 to 4 heteroatoms as ring members. Another group of heterocyclyls has from 1 to 2 heteroatoms as ring members. 30 One group of heterocyclyls has from 3 to 8 ring members in each ring. Yet another group of heterocyclyls has from 3 to 7 ring members in each ring. Again another group of heterocyclyls has from 5 to 6 ring members in each ring. "Heterocyclyl" is intended to encompass a heterocyclyl group fused to a carbocyclyl or benzo ring systems. Examples of WO 2012/013728 PCT/EP2011/062949 78 heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, 5 oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examples of heteroaryls that are heterocyclyls include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, 10 isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl. 15 As used herein, the term "heterocycloalkyl," refers to a heterocyclyl group that is not fully saturated e.g., one or more of the rings systems of a heterocycloalkyl is not aromatic. Examples of heterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl. 20 As used herein, the term "hydroxyl," as used herein, refers to -OH. As used herein, the term "hydroxyalkyl," as used herein, refers to a hydroxyl group attached to the parent molecular moiety through an alkyl group. 25 As used herein, the phrase "in the main chain," refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein. 30 As used herein, the term phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur. As used herein, the term "lower," where not otherwise specifically defined, means WO 2012/013728 PCT/EP2011/062949 79 containing from 1 to and including 6 carbon atoms. As used herein, the term "lower aryl," means phenyl or naphthyl. 5 As used herein, the term "lower heteroaryl," means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms selected from 0, S, or N. As used herein, the term "nitro," refers to -NO 2 . 10 As used herein, the terms "sulfonate" "sulfonic acid" and "sulfonic," refers to the -- SO 3 H group and its anion as the sulfonic acid is used in salt formation. As used herein, the term "sulfanyl," to -S-. 15 As used herein, the term "sulfinyl," refers to --S(=O)(R)-, with R as defined herein. As used herein, the term "sulfonyl," refers to --S(=0) 2 R, with R as defined herein. 20 As used herein, the term "sulfonamide", refers to an N-sulfonamido or S-sulfonamido group as defined herein. As used herein, the term "N-sulfonamido," refers to a RS(=0) 2 N(R')- group with R and R' as defined herein. Exemplary, non-limiting N-sulfonamido groups are -NHSO 2
CH
3 , 25 -NHSO 2
CH
2
CH
3 , -NHSO 2 (phenyl), or -NHSO 2 (isopropyl). As used herein, the term "S-sulfonamido," refers to a -S(=0) 2 NRR', group, with R and R' as defined herein. 30 As used herein, the term "urea," refers to a -N(R)C(=O)N(R) group wherein R and R' are as defined herein.
WO 2012/013728 PCT/EP2011/062949 80 As used herein, "hydrogen bonding group" refers to a substituent group, which is capable of taking part in a non-covalent bonding between hydrogen and another atom (usually nitrogen or oxygen). Examples include, but are not limited to, -NH 2 , -OH, amido, -S(O) 2
NH
2 , C(=O)NH 2 , -CH 2
-C(=O)NH
2 , - and -CH 2
-NH
2 . Other non-limiting examples include 5 NHC(=O)CH 3 or -NHCH 3 . As used herein, the term "amide isostere" refers to a monocyclic or bicyclic ring system that is isosteric or bioisosteric with an amide moiety. Examples of amide isoteres include but are not limited to those disclosed in, e.g., Meanwell (2011) J. Med. Chem. PMID: 10 21413808, As used herein, the term "optionally substituted" means the preceding or anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently 15 selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxyl, amino, lower 20 alkylamino, arylamino, aminoalkyl, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N 3 , SH, SCH 3 ,
C(O)CH
3 , CO 2
CH
3 , CO 2 H, pyridinyl, thiophene, furanyl, carbamate, and urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example 25 forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., --CH 2
CH
3 ), fully substituted (e.g., --CF 2
CF
3 ), monosubstituted (e.g., -
CH
2
CH
2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., --CH 2
CF
3 ). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a 30 substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with." In one specific definition, the optional WO 2012/013728 PCT/EP2011/062949 81 substituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, -N((Cl C3)alkyl) 2 , -NH((C1-C3)alkyl), -NHC(=O)((C1-C3)alkyl), -C(=O)OH, -C(=O)O((C1 C3)alkyl), -C(=O)(Cl-C3)alkyl), -C(=O)NH 2 , -C(=O)NH(C 1 -C3)alkyl), C(=O)NH(cycloalkyl), -C(=O)N(Cl-C3)alkyl) 2 , -S(=0) 2 ((C1-C3)alkyl), -S(=O) 2
NH
2 , 5 S(=0) 2 N((C1-C3)alkyl) 2 , - S(=0) 2 NH((C1-C3)alkyl), -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , -CF 3 , -CN, -NH 2 , -NO 2 , or tetrazolyl. As used herein, the term "optional substituent" denotes that the corresponding substituent may be present or may be absent. Accordingly, a compound having 1, 2 or 3 optional 10 substituents may be unsubstituted or may be substituted with 1, 2 or 3 substituents. The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl,. Whether an R group has a 15 number designation or not, every R group, including R, R' and RP where p=(l, 2, 3, . . . p), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. 20 Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(=O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen. 25 Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can 30 be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic WO 2012/013728 PCT/EP2011/062949 82 columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and 5 zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms. 10 As used herein, the term "optically active," refers to the ability of a compound to rotate plane polarized light. In the context of the invention, the term refers to mixtures of enantiomers which are not racemic mixtures; that is to say, not a 50:50 mixture of a (+) enantiomer and the corresponding (-) enantiomer. 15 As used herein, the term "N-substituted aryl or heteroarylcyclopropylamine" (or, likewise, "N-substituted aryl- or heteroaryl- cyclopropylamine"), refers to a compound having a 1,2 disubstituted cyclopropyl core wherein the 1 and 2 positions are substituted with an substituted amine group and a substituted aryl or heteroaryl group. Compounds of Formula 20 (II) and Formula (III) as described herein are examples of N-substituted aryl- or heteroaryl cyclopropylamines. As used herein, the term "enantiomeric excess" or "ee" or "percent enantiomeric excess" refers to the difference between the mole fraction of one specific enantiomer (i.e., the 25 specified enantiomer) and the mole fraction of the other enantiomer in relation to the sum of the mole fractions of both enantiomers, expressed as a percent value, and thus describes the extent of the excess of one specific enantiomer in relation to the other enantiomer. If, for example, a specific enantiomer is provided in the absence of the other enantiomer, the enantiomeric excess will be 100%, while a racemate comprising equal molar amounts of the 30 two enantiomers will have an enantiomeric excess of 0%. Accordingly, the "enantiomeric excess" or "ee" or "percent enantiomeric excess" is defined by the following formula: WO 2012/013728 PCT/EP2011/062949 83 (mole fraction of the specified enantiomer) - (mole fraction of the other enantiome r) 100 (mole fraction of the specified enantiomer)+ (mole fraction of the other enantiomer) As used herein, the term "preventing an increase in a symptom," refers to both not allowing a symptom to increase or worsen, as well as reducing the rate of increase in the symptom. 5 For example, a symptom can be measured as the amount of particular disease marker, i.e., a protein (e.g., cancer biomarker). In another example the symptom can be cognitive decline. Preventing an increase, according to the definition provided herein, means that the amount of symptom (e.g., protein or cognitive decline) does not increase or that the rate at which it increases is reduced. 10 As used herein, the term "treating a disease or disorder," refers to a slowing of or a reversal of the progress of the disease. Treating a disease or disorder includes treating a symptom and/or reducing the symptoms of the disease. 15 As used herein, the term "preventing a disease or disorder," refers to a slowing of the disease or of the onset of the disease or the symptoms thereof. Preventing a disease or disorder can include stopping the onset of the disease or symptoms thereof. As used herein, the term "unit dosage form" refers to a physically discrete unit, such as a capsule or tablet suitable as a unitary dosage for a human patient. Each unit contains a predetermined 20 quantity of a compound of Formula (I), (Ia), (Ib), (II) or (III) which was discovered or believed to produce the desired pharmacokinetic profile which yields the desired therapeutic effect. The dosage unit is composed of a compound of Formula (I), (Ia), (Ib), (II) or (III) in association with at least one pharmaceutically acceptable carrier, salt, excipient, or combination thereof. 25 As used herein, the term "subject" or "patient" or "individual", such as the subject in need of treatment or prevention, may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g. a horse), a primate, a simian (e.g., a monkey or 30 ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human. The meaning of the terms "eukaryote", "animal", "mammal", etc. is well known in the art and can, for example, be deduced from Wehner und Gehring (1995; WO 2012/013728 PCT/EP2011/062949 84 Thieme Verlag). In the context of this invention, it is particularly envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like 5 Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pig, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject/patient/individual is a mammal; more preferably, the subject/patient/individual is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a 10 rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutang, a gibbon, a sheep, cattle, or a pig); even more preferably, the subject/patient/individual is a human. As used herein, the term "dose" or "dosage," refers the amount of active ingredient that an 15 individual takes or is administered at one time. For example, a 40 mg dose of a compound of Formula (I), (Ia), (Ib), (II) or (III) refers to, in the case of a twice-daily dosage regimen, a situation where the individual takes 40 mg of a compound of Formula (I) twice a day, e.g., 40 mg in the morning and 40 mg in the evening. The 40 mg of a compound of Formula (I), (Ia), (Ib), (II) or (III) dose can be divided into two or more dosage units, e.g., two 20 mg 20 dosage units of a compound of Formula (I), (Ia), (Ib), (II) or (III) in tablet form or two 20 mg dosage units of a compound of Formula (I), (Ta), (Tb), (IT) or (III) in capsule form. As used herein, a "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a 25 pharmaceutically acceptable salt of such compound. As used herein, a "pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine 30 techniques known in the art and their activities determined using tests such as those described herein.
WO 2012/013728 PCT/EP2011/062949 85 As used herein, a "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react 5 with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, 10 metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, 15 phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, or mandelates. As used herein, a "pharmaceutically acceptable carrier" refers to a non-API (API refers to 20 Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency. 25 As is understood by the skilled artisan, certain variables in the list of substituents are repetitive (different name for the same substituent), generic to other terms in the list, and/or partially overlap in content with other terms. In the compounds of the invention, the skilled artisan recognizes that substituents may be attached to the remainder of the molecule via a 30 number of positions and the preferred positions are as illustrated in the Examples. As described herein above, the compound of Formula (I), (Ia) or (Ib) contains asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Thus, optical WO 2012/013728 PCT/EP2011/062949 86 isomers or enantiomers, racemates, tautomers, and diastereomers are also encompassed by the compounds of Formula (I), (Ta) or (Jb). The methods of the present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art and are furthermore 5 described in the appended examples. The present invention encompasses any isolated racemic or optically active form of compounds according to Formula (I), (Ia) or (Ib), or any mixture thereof. In one aspect, the compounds of the invention have a trans configuration around the cyclopropyl ring as in trans-phenylcyclopropylamine. In one aspect, the compounds of the invention have a cis configuration around the cyclopropyl ring as in cis 10 phenylcyclopropylamine. In a preferred aspect, the compounds of Formula (I), (Ia) or (Tb) have the trans configuration. In a more preferred aspect, the compounds of Formula (I), (Ia) or (Ib) are (-) stereoisomers having the trans configuration around the cyclopropyl ring. Typically, compounds according to Fomula (T), (Ia), (Ib), (II) or (III) can be effective at an 15 amount of from about 0.01 ptg/kg to about 100 mg/kg per day based on total body weight. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time. The suitable dosage unit for each administration can be, e.g., from about 1 pig to about 2000 mg, preferably from about 5 pig to about 1000 mg. Even more preferably, the amount of active ingredient 20 administered is from about 5 pig to about 100 mg per day. These doses will depend of the pharmacokinetic parameters of the particular compound and other ADME properties as well as the efficacy of the compound in a particular disease setting. It should be understood that the dosage ranges set forth above are exemplary only and are 25 not intended to limit the scope of this invention. The therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by 30 the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan. The amount of administration can be adjusted as the various factors change over time.
WO 2012/013728 PCT/EP2011/062949 87 For oral delivery, the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or 5 flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be orally delivered in the form of enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared in any conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as 10 fatty oil can also be included in capsules. Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included. In addition, for convenient 15 administration by enteral feeding tube in patients unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil. The active compounds can also be administered parenterally in the form of solution or 20 suspension, or in lyophilized form capable of conversion into a solution or suspension form before use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates 25 buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules. Routes of topical administration include nasal, bucal, mucosal, rectal, or vaginal 30 applications. For topical administration, the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene WO 2012/013728 PCT/EP2011/062949 88 glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. A special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference. 5 Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can 10 be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable. For purposes of this invention, hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be 15 useful. See, e.g., Phillips et al. (1984) J Pharmaceut. Sci., 73: 1718-1720. The active compounds can also be conjugated, to a water soluble non- immunogenic non peptidic high molecular weight polymer to form a polymer conjugate. For example, an active compound is covalently linked to polyethylene glycol to form a conjugate. Typically, 20 such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the active compound in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218. PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses. For example, 25 PEGylated interferon (PEG-INTRON A@) is clinically used for treating Hepatitis B. PEGylated adenosine deaminase (ADAGEN@) is being used to treat severe combined immunodeficiency disease (SCIDS). PEGylated L-asparaginase (ONCAPSPAR@) is being used to treat acute lymphoblastic leukemia (ALL). It is preferred that the covalent linkage between the polymer and the active compound and/or the polymer itself is hydrolytically 30 degradable under physiological conditions. Such conjugates known as "prodrugs" can readily release the active compound inside the body. Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art. Other pharmaceutically acceptable WO 2012/013728 PCT/EP2011/062949 89 prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. 5 Liposomes can also be used as carriers for the active compounds of the present invention. Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for 10 preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Patent No. 4,522,81 1 ; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976). The active compounds can also be administered in combination with another active agent 15 that synergistically treats or prevents the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention. Such other active agents include but are not limited to anti-inflammation agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, 20 anti-cancer drugs, hypertension drugs, and the like. Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, 25 procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins. Particularly useful members 30 of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5 fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, WO 2012/013728 PCT/EP2011/062949 90 melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT- 11, topotecan, 5 ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
WO 2012/013728 PCT/EP2011/062949 91 General Synthetic Route Description Compounds of Formula (I), (Ia), (Tb), (II) or (III) can be synthesized in accordance with or in analogy to the general routes described in Schemes 1, 2 and 3. Other routes known by 5 the ordinary skilled artisan, as well as other reactants and intermediates, can also be used to arrive at the compounds of Formula (I), (Ia), (Ib), (II) or (III). I-1BN2Me 3 S(O-I, t-BuOK ~ 8 n(R2) ()(A) MeSO uK* nR)()()NO2
(R
3 )n (R 3 )n (1) (2) Zn, HCI (aq.) 0 i-PrOH H ()(D) () R NaBH(OAC) 3 -(B, A1 n(R2) (A) N (D(R 1 ) n(R 2 ) (A) NH 2 H D (R3)n (R3)n (5) (3) 10 SCHEME 1: DMSO (Dimethyl sulfoxide) Commercially available nitrostyrenes of formula (1) have been subjected to a cyclopropanation reaction using trimetilsulfoxonium iodide and potassium tertbutylate. The 15 nitro group of the resulted trans nitrocyclopropyl derivatives of formula (2) (being trans ((IS, 2R), (lR, 2S)) mixture although the individual diastereoisomers corresponding to (IS, 2R) and (IR, 2S) can be used) has been then reduced using zinc in hydrochloric acid to afford the cyclopropylamino derivatives of formula (3). Later reductive alkylation with commercially available aldehydes of formula (4) using sodium triacetoxyborohydride as 20 reducing agent leads to the formation of cyclopropylamino derivatives of formula (5) which are subjects of the present invention.
WO 2012/013728 PCT/EP2011/062949 92 BrK ,CHO (EtO) 2
P(O)CH
2
CO
2 Et O (A) t-BuOK,THF. 0 C, 2 h Br A O (A) -Z OEt
(R
3 )n (6) (7) Me 3 S(O)-I, NaH DMSO, t.a., 2 h NaOH (ac) MeOH Br, OH t.a., 16 h Br() OEt ()(A) i (R3)n O0 (9) 1. CICO 2 Et, Et 3 N, (8) acetone, -15 *C, 1 h 2. NaN 3 , water -10 0C, 20 min Br,, Br,0 Br(A)
N
3 _Br_(A) N O 0 tBuOH H
(R
3 )n 75 C, 20 h (R3)n (10) (11) n(R2) ()B(OH)2 (12) ACN, K 2 CO3, H 2 0, Pd(PPh 3
)
4 n( (B), .,z ""'H HO!I Et 2 O ,(B) "A"l 2)((A) "NH 2 n(R 2 ) '(A) N kO I HCI / H (R\3)n (R k3)n (3) (13) (R) Br,CI (D1(1) (4) (D) (14) NaH / DMF NaBH(OAc) 3 n (R2)(B)'(A) N (f(Rl) HCI Et 2 O ( (B) ,"N O 2) 1 H(D) -n---- (R 2 ) (A) N I H (R3)n (5) (R) (D)-(R1) (15) SCHEME 2: ACN (acetonitrile), DMSO (Dimethyl sulfoxide), THF (Tetrahydrofuran).
WO 2012/013728 PCT/EP2011/062949 93 Commercially availables aldehydes of formula (6) were subjected to a Homer-Wadsworth Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofuran at 0 0 C to get the ethyl acrylate derivatives of formula (7) which is subjected 5 to cyclopropanation using trimetilsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent, leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (8) (being trans ((1S, 2R), (IR, 2S)) mixture although the individual diastereoisomers corresponding to (IS, 2R) and (IR, 2S) can be used). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (9) was 10 performed using NaOH in MeOH. Reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (10). Reaction with tert-butanol results in the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (11). The reaction with commercially available boronic acid or boronate ester derivatives of 15 formula (12) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (13). Deprotection of the Boc-group using HCl 2M in diethyl ether using diethyl ether as a 20 solvent leads to the formation of the corresponding hydrochloride salt of the (trans) cyclopropanamine derivatives of formula (9). Reductive alkylation with commercially available aldehides of formula (4) using sodium triacetoxyborohydride as reducing agent leads to the formation of cyclopropylamino derivatives of formula (5) which are subjects of the present invention. 25 The alkylation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (13) with commercial available alkyl halides of formula (14) using sodium hydride as a base and DMF as a solvent leads to the formation of the tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (15). Deprotection of the Boc-group using HC 2M in diethyl ether 30 using diethyl ether as a solvent results in the formation of the corresponding hydrochloride salt of the (trans)-cyclopropanamine derivatives of formula (5), which are subject of the present invention as defined above.
WO 2012/013728 PCT/EP2011/062949 94 (R2)n Br, CI-(B) HO (A),CHO (17)
(R
2 )- (B)O,(A)' CHO I K 2
CO
3 / DMF
(R
3 )n (R3)n (16) (18) (EtO) 2
P(O)CH
2
CO
2 Et t-BuOK,THF. 0 0C, 2 h Me 3 S(O)-I, NaH 0 (R2)nN-, (B)", O, (A OEt DMSO, t.a., 2 h (R 2 )n, (B)/Os(A): Ot (B (A)) (R3)n (20) NaOH (ac) MeOH 1. CICO 2 Et, Et 3 N, t.a., 16 h acetone, -15 *C, 1 h 2. NaN 3 water (R2)nN (B)O OH -10 0 , 20 min (R 2 )nN(B). OA , N3 (R3)n O(R 3 )n (21) (22) tBuOH 75 *C, 20 h (R2)nN(B) O'(A)
NH
2 2HI / Et 2 0 (R 2 )N()/O(A) 'N OO HI H (R3)n HCI (R)I (R 3 )n (24) (23) 0 R1 CIBr--(DR) H (D) (4) (14) NaBH(OAc) 3
K
2
CO
3 / DMF (R2)nN,,(B)" 0(A)I , *N ().(R1) | H (R3)n (25) SCHEME 3: DMF (N,N-dimethylformamide), DMSO (Dimethyl sulfoxide), THF (Tetrahydrofuran). 5 The alkylation of commercially available aldehydes of formula (16) using commercially available alkyl halides of formula (17), potassium carbonate in N,N-dimethylformamide leads to the formation of the aldehyde derivatives of formula (18). A Homer-Wadsworth- WO 2012/013728 PCT/EP2011/062949 95 Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofuran at 0 0 C gives the ethyl acrylate derivatives of formula (19) which are subjected to cyclopropanation using trimetilsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives 5 of formula (20). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (21) was performed using NaOH in MeOH. Reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (22). Reaction with tert-butanol results in the formation of tert-butyl (trans)- cyclopropylcarbamate derivatives 10 of formula (23). Boc-group deprotection using HCl 2M in diethyl ether and diethyl ether as a solvent leads to the formation of the corresponding hydrochloride salt of the (trans) cyclopropanamine derivatives of formula (24). Reductive alkylation with commercially available aldehydes of formula (4) using sodium 15 triacetoxyborohydride as a reducing agent leads to the formation of (trans) cyclopropylamino derivatives of formula (25) which are also subjects of the present invention. Alternatively, alkylation of (trans)-cyclopropanamine derivatives of formula (24) with 20 commercial available alkyl halides of formula (14) using potassium carbonate as a base and N,N-dimethylformamide as a solvent also leads to the formation of (trans) cyclopropylamino derivatives of formula (25), which are subject of the present invention as defined above. 25 As known by those skilled in the art, (trans)-cyclopropylamino derivatives of formula (5) and (25) can also be obtained from the (trans)-cyclopropanamine derivatives of formula (3) and (24), respectively, by a well-known reactions (i.e, cyclization). Optically pure or enantiomerically enriched compounds can be isolated at various stages of 30 the synthetic procedure and can be used in subsequent steps.
WO 2012/013728 PCT/EP2011/062949 96 Examples The program used to generate the names corresponding to the structures in the Example 5 compounds below was ChemBioDraw Ultra 11.0.1. This program named the molecules as the (1 S,2R) configuration due to the configuration of the input structure and the "trans" term has been substituted in the place of the (1S,2R) term specified by the program. The structures depicted below for the Example compounds below are shown as having one particular stereochemical configuration around the cyclopropyl carbon atoms of the 10 phenylcyclopropylamine core (IS, 2R). Unless stated otherwise, the compounds synthesized in the Examples are mixtures having both configurations (IR, 2S) and (1S, 2R), that is to say they are "trans" in respect to the substituents on the cyclopropyl ring system. This is due to the fact the cyclopropyl derivatives used as starting material are "trans". It is contemplated that the cis configuration starting material or the individual diastereomers 15 could be used as starting material, all of which are either commercially or synthetically available. Thus, the invention relates to compounds of Formula (I), (Ia), (Ib), (II) or (III), including those of the examples, that have specific stereochemical configurations around the cyclopropyl ring e.g., trans ((iR, 2S) and (IS, 2R)) and cis ((1R, 2R) and (IS, 2S)). A preferred stereochemical configuration around the cyclopropyl ring is trans. 20 The compounds of the examples can also be synthesized or provided in a salt form. The skilled artisan is aware and capable of making salt forms and/or converting salt forms of the compounds of the invention, e.g., compounds of Formula (I), (Ia), (Ib), (II) or (III) and those of the Examples. In some cases the compounds of Formula (I), (Ia), (Ib), (II) or (III) and the 25 Examples can be more stable as salt forms as compared to free base. In reference to the synthetic schemes described herein the following intermediates (and analogous intermediates or derivatives thereof) can be made using the following procedures.
WO 2012/013728 PCT/EP2011/062949 97 Intermediate A: 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene NO 2 Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t 5 BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy) 4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et 2 0 (3x10 mL); the organic layers were washed with brine (2x15 mL), dried over anhydrous Na 2
SO
4 and filtered. After removal of the 10 solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1 -(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf- 0.5 (20% EtOAc/hexanes), white solid, 26% yield]. Intermediate B: Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine
NH
2 15 Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1 -(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A, 0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 20 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH 2 C1 2 (3x15 mL). The organic layers were dried over anhydrous Na 2
SO
4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH 2
CI
2 ) affording 0.50 g of (trans)-2-[4 25 (benzyloxy)phenyl]cyclopropanamine [Rf- 0.2 (10% MeOH/CH 2 Cl 2 ), white solid, 70% WO 2012/013728 PCT/EP2011/062949 98 yield]. 1 H-NMR (MeOH, 250 MHz, 8): 7.45-7.27 (in, 5H, ArH); 6.96 (d, J= 8.5 Hz, 2H, ArH); 6.86 (d, J= 8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (in, 1H, CH); 1.86-1.76 (in, 1H, CH); 0.98-0.85 (in, 2H, CH2). 5 Intermediate C: (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate 0 OEt Br N Triethyl phosphonoacetate (26.6g, 118.8 mmol) was added slowly dropwise to a mixture of Potassium-tert-butoxide (14.5g, 129.6 mmol) in dry THF (200 mL) at -5 'C, stirred for 20 10 min and then a solution of 6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL) was added slowly dropwise at -5 'C and stirred for 30 min. After completion, the reaction mixture was poured into ice water (350 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with saturated NaHCO 3 solution (250 mL), water (250 mL) and brine (250 mL) and dried over anhydrous Na 2
SO
4 , filtered and 15 evaporated to get (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (20 g, 72.9 %) as brown color liquid. This is carried to next step without further purification. Intermediate D: (Trans)-ethyl-2-(6-bromopyridin-3 -yl)cyclopropanecarboxyl ate - OEt 0 20 Br N Trimethyl sulfoxonium iodide (20.8g, 94.7 mmol) was added in small portions to a suspension of sodium hydride (4g, 170.6 mmol) in dry DMSO (400 mL) at rt., stirred for 1 h until clear solution was obtained. A solution of (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate 25 (Intermediate C, 20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h.
WO 2012/013728 PCT/EP2011/062949 99 After completion, the reaction mixture was poured into ice water (700 mL), extracted with EtOAc (2 x 350 mL). The combined organic extracts were washed with water ( 250 mL), brine (250 mL) and dried over anhydrous Na 2
SO
4 , filtered and evaporated to give (trans) ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10g, 47 %) as brown liquid. 5 Intermediate E: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride -, OH 0 Br N .HCI 10 NaOH 4N solution (60 mL) was added to a solution of (trans)-ethyl-2-(6-bromopyridin-3 yl)cyclopropanecarboxylate (Intermediate D, 10 g, 37.1 mmol) in methanol (100 mL) and the reaction mixture was stirred at RT for 4 h. After completion, the solvent was evaporated and the residue was diluted with ice water (250 mL) and acidified with 4 N HCl solution, the aqueous layer was extracted with EtOAc (2 x 350 mL). The combined organic extracts 15 were washed with water ( 250 mL), brine (250 mL) and dried over anhydrous Na 2
SO
4 , filtered and evaporated to give (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (5g, 55.8 %) as a light brown color solid. Intermediate F: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide 20 . N3 K-o Br N Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of (trans)-2-(6 25 bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (Intermediate E, 5 g, 20.7 mmol) and Et 3 N (14,2 mL, 103.7 mmol) in Acetone (100 mL) at -5 'C, then reaction WO 2012/013728 PCT/EP2011/062949 100 mixture was stirred at -5 'C for 1 h, then a solution of NaN 3 (2.7g, 41.4 mmol) in water (10 mL) was added and stirred for 30 mins at RT. After completion the solvent was evaporated under vacuum. The crude residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), brine (80 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated to get 5 (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5 %) as a brown color gummy liquid. Intermediate G: tert-butyl (trans)-2-(6-bromopyridin-3 -yl)cyclopropylcarbamate 0 N O H 10 Br N A solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbony azide (Intermediate F, 2.5 g, 9.36 mmol) in tert-butanol (80 mL) was heated at 90 'C for 16 h. After completion, the solvent was evaporated under vacuum and the residue was taken in water (100 mL) and 15 extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by flash column chromatography (SiO 2 ) by eluting with EtOAc: Hexane (2: 8) to get tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (1.1g, 37.5 %) as a light yellow solid. 'H-NMR (CDCl 3 ) 8 (ppm): 1.16 (q, 1H), 1.23 (quin, 1H), 20 1.45 (s, 9H), 2.01 (in, 1H), 2.69 (in, 1H), 4.88 (br, 1H), 7.36 (s, 2H), 8.20 (s, 1H). Intermediate H: (E)-ethyl 3-(4-bromophenyl)acrylate 0 OEt Br 25 WO 2012/013728 PCT/EP2011/062949 101 A solution of triethyl phosphonoacetate (13.1 g, 0.0589 mol) was added slowly (dropwise) to a solution of Potassium-tert-butoxide (6.59 g, 0.0589 mol), in dry THF (150 mL) at -5 'C, stirred for 30-45 mins at the same temperature, then a solution of 4-Bromo benzaldehyde (10 g, 0.054 mol), in dry THF (50 mL) was 5 slowly added dropwise at -5 'C over a period of 15 mins, stirred the reaction mixture for 30 mins at the same temperature. After completion of reaction by TLC, the reaction mixture was poured into ice water (300 mL), extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with sat NaHCO 3 solution (200 mL), water (200 mL), brine (200 mL) and dried over anhydrous Na 2
SO
4 , 10 filtered and evaporated to get crude (E)-ethyl 3-(4-bromophenyl) acrylate (10 g, 72 %) as pale green liquid. This is carried to next step without further purification. Intermediate I: (Trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate OEt 0 15 Br Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly in small portions over a period of 20 min. to a suspension of sodium hydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h, till the formation of clear solution. Then a solution of 20 (E)-ethyl 3-(4-bromophenyl) acrylate (Intermediate H, 5 g, 0.01968), in dry DMSO (20 mL) was added slowly dropwise, stirred at rt for 30 mins. After completion of reaction, checked by TLC, the reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2 x 150 mL). Combined organic extracts were washed with ice water (2 x 150 mL), brine (150 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated to get (trans)-ethyl 2-(4 25 bromophenyl)cyclopropanecarboxylate (4 g, 75.9 %) as a green liquid. The crude is carried to next step without further purification. Intermediate J: (Trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid WO 2012/013728 PCT/EP2011/062949 102 -, i OH Br NaOH 4N (20 mL) was added to a solution of (trans)-ethyl 2-(4 bromophenyl)cyclopropanecarboxylate (Intermediate I, 4 g, 0.0149 mol), in Methanol (40 5 mL) and stirred at rt for 2 h. After completion of reaction, checked by TLC, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with HCl 4 N solution, the solid formed was filtered and dried to get (trans)-2-(4 bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72 %), as a white solid. 10 Intermediate K: (Trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide ".."ir N3 Br Ethyl chloroformate (1.9 mL) was added to a solution of (trans)-2-(4-bromophenyl) 15 cyclopropanecarboxylic acid (Intermediate J, 4 g, 0.0165 mol) and Et 3 N (2.51 mL, 0.0199 mol) in acetone (60 mL) at -20 'C, stirred at same temperature for 1 h, then a solution of NaN 3 (1.3 g, 0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt. After completion of reaction, checked by TLC, the solvent was evaporated and crude residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), dried over anhydrous 20 Na 2
SO
4 , filtered and evaporated to get (trans)-2-(4-bromophenyl)cyclopropanecarbony azide (4 g). The crude residue is carried to next step without further purification. Intermediate L: tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate 0 N 25 Br H WO 2012/013728 PCT/EP2011/062949 103 A solution of (trans)-2-(4-bromophenyl) cyclopropanecarbonyl azide (Intermediate K, 4 g) in tert-Butanol (40 mL) was heated at 90 'C for 16 h. After completion of reaction, checked by TLC, the solvent was evaporated residue was poured into water (50 mL), extracted with 5 EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by column chromatography (SiO 2 ) by eluting with EtOAc: Pethroleum ether (2: 98), to get tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate (2.5 g, 48 % overall 2 steps) as a white solid. 'H-NMR (CDC1 3 , 250 MHz) 6 (ppm): 1.07-1.19 (in, 2H), 1.44 (s, 10 9H); 2.05-1.94 (in, 1H); 2.72-2.62 (in, 1H); 4.85 (br, 1H); 7.09-6.96 (in, 2H); 7.44-7.33 (in, 2H). Intermediate M: Ethyl 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate N-N NBoc 15 ( Sodium hydride (280 mg, 0.007 mol) in DMF (10 mL) was added to a suspension of Ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (1 g, 0.006 mol) in DMF (2 mL) at 0 'C, stirred for 10 mins, then Di tert-butyl dicarbonate (1.65 g, 0.0076 mol) was added and stirred at RT for 20 16 h. After completion, the reaction mixture was poured into ice water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with cold water (2 x 25 mL), brine (25 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by column chromatography (SiO 2 ) using EtOAc: Petroleum ether (1:3) as eluent to get Ethyl 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate (900 25 mg, 56.2 %) as a white solid. Intermediate N: Tert-butyl (5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)carbamate WO 2012/013728 PCT/EP2011/062949 104 N-N -O' N Boc HO H NaBH 4 (330 mg, 0.0087 mol) was added to a solution of Ethyl 5-((tert butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate (Intermediate M, 900 mg, 0.0035 5 mol) in THF (18 mL) at 0 'C and stirred at RT for 16 h. After completion, the solvent was evaporated and the residue was taken in water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by column chromatography (SiO 2 ) using EtOAc: Petroleum ether (8: 2) as eluent to get tert-butyl (5 10 (hydroxymethyl)-1,3,4-oxadiazol-2-yl) carbamate (450 mg, 54.2 %) as a white solid. Intermediate 0: Tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate N--N H O N Boc o H 15 MnO 2 (500 mg) was added to a solution of tert-butyl (5-(hydroxymethyl)-1,3,4-oxadiazol-2 yl) carbamate (Intermediate N, 450 mg, 0.0021 mol) in THF (9 mL) at RT and stirred for 16 h. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was evaporated to get crude tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate (250 mg). 20 This crude was carried to next step without further purification. Intermediate P: 4-(benzyloxy)benzaldehyde H O BnO 25 Potassium Carbonate (678 g, 4.91 mol) was added to a solution of 4-hydroxybenzaldehyde (200 g, 1.63 mol) in DMF (2 L) followed to the addition of benzyl bromide (214 mL, 1.80 WO 2012/013728 PCT/EP2011/062949 105 mol) at 0' C and stirred for 18 h at RT. After completion, the reaction mixture was poured into ice water (3 L), filtered the solid and dried to get 4-(benzyloxy)benzaldehyde (230 g, 66 % ). 5 Intermediate Q: (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate 0 OEt BnO Triethyl phosphonoacetate (259 mL, 1.3 mol) was added slowly drop wise to a solution of 10 Potassium-tert-butoxide (145 g, 1.29 mol) in dry THF (2 L) at -5 'C and stirred for 30-45 mins. Then a solution of 4-(benzyloxy)benzaldehyde (Intermediate P, 230 g, 1.08 mol) in dry THF ( 1.5 L) was added slowly drop wise at -10 'C over a period of 15 mins and stirred for 30 mins. After completion, the reaction mixture was poured into ice water (1 L) and extracted with EtOAc (2 x 1.5 L). The combined organic extracts were washed with sat 15 NaHCO 3 solution (1 L ), water (1 L), brine (1 L), dried over anhydrous Na 2
SO
4 , filtered and evaporated to get crude (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (290 g, 95 %). The crude was carried to next step without further purification. Intermediate R: (Trans)-ethyl 2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate 20 " OEt BnO 0 Trimethyl sulfoxonium iodide (224 g, 1.02 mol) was added portion wise to a suspension of NaH (40.8 g, 1.02 mol) in dry DMSO (2 L) at RT over a period of 20 min and stirred for 1 h 25 till the formation of a clear solution. A solution of (E)-ethyl 3-(4-(benzyloxy) phenyl) acrylate (Intermediate Q, 240 g, 0.85 mol) in dry DMSO (2 L) was added drop wise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water WO 2012/013728 PCT/EP2011/062949 106 (2 L), extracted with EtOAc (2 x 1 L). Combined organic extracts were washed with ice water (1 L), brine (1 L), dried over anhydrous Na 2
SO
4 , filtered and evaporated to afford (Trans)-ethyl 2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (142 g, 58.6 %) as an off white solid. The crude was carried to next step without further purification. 5 Intermediate S: (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylic acid AOH BnO 0 10 4N NaOH solution (4 L) was added to a solution of (trans)-ethyl 2-(4 (benzyloxy)phenyl)cyclopropanecarboxylate (Intermediate R, 250 g, 0.844 mol) in Methanol (1.2 L) at 0 'C and stirred at RT for 4 h. After completion, the solvent was evaporated, the residue was diluted with water (1 L), acidified with 4 N HCl solution, extracted with EtOAc (2 x 2 L). Combined organic extracts were washed with water (1 L), 15 brine ( I L), dried over anhydrous Na 2
SO
4 , filtered and evaporated to afford (trans)-2-(4 (benzyloxy)phenyl)cyclopropanecarboxylic acid (190 g, 84 %) as off white solid. The crude was carried to next step without further purification. Intermediate T: (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide 20 "A N 3 BnO Ethyl chloroformate (143 mL, 1.48 mol) was added to a solution of (trans)- 2-(4 (benzyloxy) phenyl) cyclopropanecarboxylic acid (Intermediate S, 190 g, 0.70 mol), 25 Triethyl amine (229 mL, 1.63 mol) in acetone ( 2.8 L) at -20 'C and stirred for 1 h, then a solution of NaN 3 ( 138 g, 2.1 mol) in water (200 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, residue was dissolved in EtOAc (2 L), WO 2012/013728 PCT/EP2011/062949 107 washed with water (2 L), brine ( 1 L), dried over anhydrous Na 2
SO
4 , filtered and evaporated to afford (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide ( 178 g, 85.9 0 Intermediate U: Tert-butyl ((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate 5 0 'N O H BnOH A solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide (Intermediate T, 178 g, 0.64 mol) in tert-butanol (2.6 L) was heated at 90 'C for 16 h. After completion, the 10 solvent was evaporated and the crude residue was purified by column chromatography by using (SiO 2 ) EtOAc: Pet ether (4: 96) to get tert-butyl ((trans)-2-(4 (benzyloxy)phenyl)cyclopropyl)carbamate (78 g, 37.8 %) as off-white solid. Intermediate V: (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine hydrochloride
NH
2 15 BnO HCI HCl in Dioxane (390 ml) was added to a solution of tert-butyl ((trans)-2-(4 (benzyloxy)phenyl)cyclopropyl)carbamate (Intermediate U, 78 g, 0.23 mol) in 1,4-dioxane (780 mL) at 0 'C and stirred at RT for 12 h. After completion, the solvent was evaporated 20 and the residue was triturated with diethyl ether (1 L) followed by hexane (1 L) to give (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine hydrochloride (55 g, 87 %) as off-white solid. Intermediate W: ethyl 2-amino-2-thioxoacetate 25 WO 2012/013728 PCT/EP2011/062949 108 O O ,, NH 2 S
P
2
S
5 (28.5 g, 128 mmol) was added portion wise to a solution of ethyl 2-amino-2-oxoacetate (30 g, 25.6 mmol) in pyridine (300 mL) over a period of 30 mins, and stirred at 90'C for 3 5 h. After completion, the solvent was evaporated, the residue was diluted with water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined extracts were washed with water (2 x 200 mL), brine (200 mL) and dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude was purified by column chromatography (SiO 2 ) by eluting (1:9) EtOAc:Hexane to afford ethyl 2-amino-2-thioxoacetate (18 g, 52.9 %) as white solid. 10 Intermediate X: 2-(ethoxycarbonyl)thiazole-5-carboxylic acid O0 0 OH 15 Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2 thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHCO 3 and extracted with EtOAc (2 x 250 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (2 x 250 mL). The combined extracts were 20 washed with water (250 mL), brine (250 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification. Intermediate Y: Ethyl 5-(azidocarbonyl)thiazole-2-carboxylate 25 WO 2012/013728 PCT/EP2011/062949 109 Oo 0
N
3 Ethyl chloroformate (9.8 g, 83.6 mmol) was added to a solution of 2 (ethoxycarbonyl)thiazole-5-carboxylic acid (Intermediate X, 13 g, 64.67 mmol), TEA (9.79 5 g, 97.01 mmol) in acetone (130 mL) at -20 0 C, stirred for 1 h, then a solution of NaN 3 (5.4 g, 83.6 mmol) in water (15 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, the crude residue was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated to afford Ethyl 10 5-(azidocarbonyl)thiazole-2-carboxylate (11 g crude) as brown liquid. The crude was carried to next step without further purification. Intermediate Z: Ethyl 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate 15_NHBoc 150 A solution of ethyl 5-(azidocarbonyl)thiazole-2-carboxylate (Intermediate Y, 11 g, 48.6 mmol) in tert-butanol (150 mL) was refluxed at 90 'C for 16 h. After completion, the solvent was evaporated. The crude residue was purified by column chromatography by 20 using (SiO 2 ), eluting with EtOAc: Petroleum ether (2:98) to afford Ethyl 5-((tert butoxycarbonyl)amino)thiazole-2-carboxylate (4 g, 30.23 %) as white solid. Intermediate AA: Tert-butyl (2-(hydroxymethyl)thiazol-5-yl)carbamate N It 3 NHBoc 25
HO
WO 2012/013728 PCT/EP2011/062949 110 NaBH 4 (1.1 g, 29.2 mmol) was added portion wise to a solution of Ethyl 5-(tert butoxycarbonyl amino)thiazole-2-carboxylate (Intermediate Z, 4 g, 14.6 mmol) in MeOH (40 mL) at 0 0 C over a period of 30 mins and stirred at RT for 16 h. After completion, 5 solvent was evaporated, the solid residue was dissolved in ice water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude was purified by column chromatography by using SiO 2 , eluting with EtOAc:Petroleum ether (2:8) to afford Tert-butyl (2-(hydroxymethyl)thiazol-5-yl)carbamate (2.9 g, 84.8 % ) as white solid. 10 Intermediate AB: Tert-butyl (2-formylthiazol-5-yl)carbamate HN S\ NHBoc 0 15 MnO 2 (1.5 g, 18.2 mmol) was added to a solution of Tert-butyl (2-(hydroxymethyl)thiazol 5-yl)carbamate (Intermediate AA, 700 mg, 3.04 mmol) in DCM (15 mL) and stirred at RT for 16 h. After completion reaction mixture was diluted with DCM, filtered through celite. The filtrate was concentrated under vacuum to afford Tert-butyl (2-formylthiazol-5 yl)carbamate (500 mg crude). The crude was carried to next step without further 20 purification. The compounds described in examples 1-24 are racemic, that is to say a 50:50 mixture of the enantiomers corresponding the trans racemate. Example 1: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin 25 -2-amine N N H 0." N NH 2 WO 2012/013728 PCT/EP2011/062949 111 Sodium triacetoxy borohydride (883 mg, 4.166 mmol) was added slowly at 0 'C to a solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine (Intermediate B, 500 mg, 2.083 mmol), 2-aminopyrimidine-5-carbaldehyde (256 mg, 2.083 mmol) in DCE (10 mL) and stirred for 20 h. After completion, the solvent was evaporated. The residue was 5 dissolved in Methanol (15 mL), NaBH 4 (237 mg, 6.249 mmol) was added slowly at 0 'C and stirred for 3 h. After completion, the solvent was evaporated, the residue was dissolved in ice water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by prep HPLC to afford 5-(((trans)-2-(4 10 (benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine (180 mg, 25 %) as white solid.
1 H-NMR (400 MHz, DMSO-d6) 6 (ppm): 0.85 (q, 1H), 0.90 (quin, 1H), 1.73 (in, 1H), 2.07 (in, 1H), 2.75 (brs, 11), 3.53 (s, 2H), 5.04 (s, 2H), 6.46 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.33 (m, 1H), 7.42 (in, 4H), 8.11 (s, 2H). Mass (M+H): 347.3 15 Following example has been synthesized using the procedure described for Example 1 and the corresponding starting materials. Example 2: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine hydrochloride 20 "N 0 HCI \
NH
2 'H-NMR (400 MHz, DMSO-d6) 6 (ppm): 1.22 (q, 1H), 1.48 (quin, 1H), 2.46 (in, 111), 2.80 (br, 1H), 4.35 (s, 2H), 5.08 (s, 2H), 6.93 (d, 2H), 7.06 (d, 2H), 7.32 (in, 2H), 7.40 (m, 4H), 25 8.98 (br, 11), 9.90 (br, 2H). Mass (M+H): 351.9 The following compounds can be synthesized following the methodology described in Scheme 1 and 2 or other synthetic routes known to the ordinary skilled artisan.
WO 2012/013728 PCT/EP2011/062949 112 Example 3: 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)pyrimidin-2-amine N N H N NNH CF3 5 Example 4: 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)thiazol-2-amine H
NH
2 CF3 10 Example 5: 3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2 yl)phenol N N ~ "H N
NNH
2 OH 15 Example 6: 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2 yl)phenol WO 2012/013728 PCT/EP2011/062949 113 H
NH
2 OH Example 7: 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol 5 N N H OH Example 8: 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol H N S_
NH
2 10 OH Example 9: 5 -(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,2,4-oxadiazol 3-amine WO 2012/013728 PCT/EP2011/062949 114 "NN/ NH2 H Example 10: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,3,4 oxadiazol-2-amine 5 H N IO
NH
2 This compound can be synthesized following scheme 1 or scheme 3, or other synthetic routes known to the ordinary skilled artisan. 10 Scheme 1 Procedure Step 1: Tert-butyl (5-fornyl-1,3,4-oxadiazol-2-yl)carbamate (Intermediate 0, 220 mg, 1.041 mmol) and sodium triacetoxy borohyride (441 mg, 2.08 mmol) was added to a solution of Trans-2 15 [4-(benzyloxy)phenyl]cyclopropanamine (Intermediate B, 250 mg,1.041 mmol) in dry Dichloro ethane (2.5 mL) at 0 0 C and stirred at RT for 24 h, then the solvent was evaporated. The residue was taken in MeOH (2.5 mL) and NaBH 4 (116 mg, 3.138 mmol) was added at 0 0 C and stirred for 2 h at RT. After completion, the solvent was evaporated, the residue was taken in water (10 mL) and extracted with EtOAc (4 x 10 mL). Combined 20 extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The residue was purified by column chromatography (SiO 2 ) using MeOH:CHCl 3 (1:99) to get tert-butyl (5-((((trans)-2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (70 mg, 15.3 %) as pale green liquid. 25 WO 2012/013728 PCT/EP2011/062949 115 Step 2: HCl in 1, 4 dioxane (1 mL) was added to a solution of tert-butyl (5-((((trans)-2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol-2-yl)carbamate (100 mg) in 1, 4 dioxane (1 mL) at 0 'C and stirred for 18 h. After completion, the solvent was 5 evaporated and residue was dissolved in water (10 mL), basified with Na 2
CO
3 solution, extracted with EtOAc (3 X 5 mL). The combined extracts were washed with water (5 mL), brine (5 mL), dried over anhydrous Na 2
SO
4 , filtered and evaporated. The crude residue was purified by column chromatography using MeOH: CHCl 3 (5:95) as eluent to afford 5 (((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine (40 10 mg, 52 %) as a white solid. 'H-NMR (400 MHz, DMSO-d6) 6 (ppm): 0.85 (in, 2H), 1.72 (in, 1H), 2.2 (in, 1H), 3.0 (in, 1H), 3.75 (s, 2H), 5.08 (s, 2H), 6.8-7.0 (in, 6H), 7.4 (in, 5H); Mass (M+H): 337.1 Scheme 3 Procedure 15 This compound can be synthesized following the same method as described in the Scheme 1 procedure but, in Step 1, the intermediate V is used instead of intermediate B. The following compounds can be synthesized following the method described for example 10 using Scheme 3 procedure and the corresponding commercial available alkyl halides to 20 get the suitable Intermediate P derivatives. Example 11: 5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine 25 N N H ON F 0"
NH
2 WO 2012/013728 PCT/EP2011/062949 116 'HNMR (400 MHz, DMSO d6) 6 (ppm): 0.84 (m, 2H), 1.79 (m, 1H), 2.20 (m, 1H), 3.12 (m, 1H), 3.78 (s, 1H), 5.02 (s, 2H), 6.85-7.00 (m, 6H), 7.2 (t, 2H), 7.46 (t, 2H); Mass (M-H): 353.3 5 Example 12: 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine "/N N
NH
2 F 10 'HNMR (400 MHz, DMSO d6) 6 (ppm): 0.85 (m, 2H), 1.73 (m, 1H), 2.19 (m, 1H), 3.00 (m, 1H), 3.75 (s, 2H), 5.07 (s, 2H), 6.85-7.00 (m, 6H), 7.14 (t, 1H), 7.25 (t, 2H), 7.41 (m, 1H); Mass (M-H): 353.3 15 Example 13: 5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine N N F O H
NH
2 F 20 HNMR (400 MHz, DMSO d6) 6 (ppm): 0.87 (m, 2H), 1.75 (m, 1H), 2.20(m, 1H), 3.04 (m, 1H), 3.75 (s, 2H), 5.13 (s, 2H), 6.80-7.05 (m, 6H), 7.16 (m, 3H); Mass (M+H): 373.0 WO 2012/013728 PCT/EP2011/062949 117 Example 14: 5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine "'NN HN 0 CNH 2 1 HNMR (400 MHz, DMSO d6) 6 (ppm): 0.86 (m, 2H), 1.73 (m, 1H), 2.18 (m, 1H), 2.98 (m, 1H), 3.75 (s, 2H), 5.05 (s, 2H), 6.82-6.95 (m, 6H), 7.44 (m, 4H); Mass (M-H): 369.0 10 Example 15: 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine "N O O
NH
2 CI 15 'HNMR (400 MHz, DMSO d6) 6 (ppm): 0.85 (m, 2H), 1.73 (m, 1H), 2.19 (m, 1H), 3.00 (m, 1H), 3.75 (s, 2H), 5.07 (s, 2H), 6.84-7.02 (m, 6H), 7.39-7.54 (m, 4H); Mass (M+H): 371.0 The following compounds can be synthesized following the methodologhy described in 20 Scheme 1, 2 and 3. Alternatively, as known by those skilled in the art, the following compounds can also be obtained from the (trans)-cyclopropanamine derivatives of formula (3) and (24), respectively, by a well-known reactions (i.e., heterocycle formation or cyclization) WO 2012/013728 PCT/EP2011/062949 118 Example 16: 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl) 1,3,4-oxadiazol-2-amine "N H H 0 e
NH
2 5 Example 17: 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl 1,3,4-oxadiazol-2-amine 10 "' N 0 N/ H N N 01 Example 18: N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 15 oxadiazol-2-yl)acetamide 0 N' 0 "Y\/NH 20 Example 19: 4'-((trans)-2-(((5 -amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl) [1,1'-biphenyl]-3-ol WO 2012/013728 PCT/EP2011/062949 119 ""I,0 / NH 2 N'N OH Example 20: 5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol-2-amine 5 N O NH 2 N NN
CF
3 Example 21: 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 10 thiadiazol-2-amine N N N 0
NH
2 15 Example 22 : 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5 amine WO 2012/013728 PCT/EP2011/062949 120 N N H 2 H-NN Example 23: 4-((((trans)-2-(3'-(trifluoromethyl)-[,1 '-biphenyl]-4 yl)cyclopropyl)amino)methyl)thiazol-2-amine 5 N N N S
CF
3 10 Example 24: 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazo-5 amine "'I'0 N N H 2 17 HN Nj 0 15 Example 25: 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5 amine H N H 2 0 7j WO 2012/013728 PCT/EP2011/062949 121 Example 26: 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N dimethyl-1,3,4-oxadiazol-2-amine 'N N N 0_ cro
N
5 Example 27: 3 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,2,4 oxadiazol-5-amine O N H2 0e
N-
0 10 Example 28: 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4 thiadiazol-3-amine H s/ NH2 15 Example 29: 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2 amine O"'N H 0N NH 2 WO 2012/013728 PCT/EP2011/062949 122 Example 30: 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3 amine O NH2 oe H NH 2 5 Example 31: 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2 amine ""'N o H - NH 2 10 Example 32: 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5 amine "N 15 N0 NH 2 Example 33: 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin 3-amine 2N N N 0 N NH 2 20 WO 2012/013728 PCT/EP2011/062949 123 Example 34: 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin 6-amine 5 N N O H NH 2 Example 35: Preparation of enantiomerically enriched or optically active compounds 10 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine can be synthesized according to the procedure describe in example 10. Alternatively, enantiomerically enriched or pure intermediates can be prepared and then used in subsequent reactions in order to synthesize the corresponding (-) or (+) enantiomer, e.g., of 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine. 15 Step 1 R-(-)-Mandelic acid (22.2 g, 0.14 mol) was added to a solution of (trans)-2-(4 (benzyloxy)phenyl)cyclopropanamine hydrochloride (intermediate V) (35 g, 0.14 mol) in a mixture of THF and H 2 0 (6: 4) (650 mL) and refluxed for 1 h. After formation of a clear 20 solution the reaction mixture was cooled to RT. The solid precipitated formed was filtered, basified with sat. NaHCO 3 solution and extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with water (500 mL), brine (500 mL), dried over anhydrous Na 2
SO
4 , filtered and concentrated under vacuum to afford trans 2-(4 (benzyloxy)phenyl)cyclopropanamine (enantiomer-(-) ) (14 g, 46.6 %) as an off white solid. 25 Step 2 Tert-butyl (5-(chloromethyl)-1,3,4-oxadiazol-2-yl)carbamate (141 mg, 0.606 mmol) was added to a solution of 2-(4-(benzyloxy)phenyl)cyclopropanamine (enantiomer (-)) (145 mg, 0.606 mmol) and K 2
CO
3 (166 mg, 1.213 mmol) in dry DMF (1.5 mL) and stirred at RT for 30 2 h. After completion, the reaction mixture was poured into ice water (10 mL) and extracted WO 2012/013728 PCT/EP2011/062949 124 with EtOAc (4 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), brine (10 mL), dried over anhydrous Na 2
SO
4 , filtered and concentrated under vacuum. The residue obtained was purified by column chromatography (SiO 2 ) using MeOH:CHCl 3 (1:99) as eluent to afford tert-butyl (5-(((2-(4 5 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (enantiomer-(-)) (100 mg, 37.7 %) as a pale green liquid. Step 3 To a solution of (-) tert-butyl 5-(((trans)-2-(4 10 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-yl carbamate (100 mg, 0.229 mmol ) in 1, 4 dioxane (1 mL) at 0 'C was added HC in 1, 4 dioxane (1 mL) and stirred for 18 h. After completion, the solvent was evaporated and residue was dissolved in water (10 mL), basified with Na2CO3 solution, extracted with EtOAc (3 X 5 mL). The combined extracts were washed with water (5 mL), brine (5 mL), dried over anhydrous 15 Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography using MeOH: CHCl3 (5: 95) as the eluent to afford (-) 5-(((trans)-2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine (40 mg, 52%) as a white solid. 20 1 HNMR (400 MHz, DMSO d6) 6: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H), 0.92 (in, 2H) Mass (M+H): 337.1 HPLC Purity: 96.02 % Chiral HPLC Purity: 95.12 % 25 Specific optical rotation [MoD2.2 (c=0.5 % in DMSO): - 37.76' The corresponding enantiomer-(+) can be synthesized by following the same procedure but using S-(+)-Mandelic acid in Step 1. 30 1 H-NMR (400 MHz, DMSO d6) 6: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H), 0.92 (in, 2H); Mass (M+H): 337.1 HPLC Purity: 98.16 % WO 2012/013728 PCT/EP2011/062949 125 Chiral HPLC Purity: 98.34 % Specific optical rotation [a]D 26
.
9 (C=0.5 % in DMSO): + 37.76' Salts for chiral recrystallization include S (+) Mandelic acid, 5 D (-) tartaric acid, L (-) di-p-toluoyl tartaric acid, or R (-) Mandelic acid. The following compounds can be prepared according to the synthetic description provided 10 herein and the skill of an ordinary skilled artisan, wherein the absolute configuration is as specified in the drawn structure: 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine N N 00/
NH
2 F 15 5 -((((trans)-2-(4-((3 -fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine N OjH N
NH
2 F 20 5 -((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-amine WO 2012/013728 PCT/EP2011/062949 126 O . " NN
NH
2 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol 2-amine 5 N H. 0 H
NH
2 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl- 1,3,4-oxadiazol 2-amine 10 N Hi N NH 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl- 1,3,4-oxadiazol 2-amine 15 N H 0 N NH N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol-2 yl)acetamide 20 WO 2012/013728 PCT/EP2O1 1/062949 127 N N H N 00 NH
-
0 N-(5-((((trans)-2-(4-(benzyloxy)pheny1)cyclopropyl)amino)methyl)> 1,3 ,4-oxadiazol-2 yl)acetamide 5 H N _ NH ~0 5 -((((trans) -2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine '7 ////N '^* N H 10 0N
NH
2 5 -((((trans) -2-(4-(benzyloxy)phenyl)cyclopropyl)amino)rnethyl) pyrimidin-2-amine N C N H 0 N NH 2 15 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3 ,4-thiadiazol-2-amine WO 2012/013728 PCT/EP2011/062949 128 H N
NH
2 5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-thiadiazol-2-amine 5 N 0 s /
NH
2 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1,3,4 oxadiazol-2-amine 10 NN H /N 00
N
5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1,3,4 oxadiazol-2-anine 15 N Q^ N- WO 2012/013728 PCT/EP2011/062949 129 Example 36: Isolation of single enantiomers of (trans) racemic N-substituted aryl- or heteroaryl-cyclopropylamine compounds 5 Chiral HPLC: Conditions to perform the chiral separation of compounds or intermediates of the invention can be similar to the following: Separation by chiral preparative HPLC: Every injection is prepared from e.g., about 15 mg of the N-substituted aryl- or heteroaryl- trans-cyclopropylamine compound dissolved in a 10 mixture of EtOH, n-pentane and HFIPA (1,1,1,3,3,3-Hexafluoro-2-propanol). The optically active N-substituted aryl- or heteroaryl- trans-cyclopropylamine compound (e.g., (-) 5 (((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine) can be separated on e.g., a ChiralPak- IA (250 X 20 mm ID) 5 pm at ambient temperature eluting with 0.1% DEA in 70/30 hexane/EtOH at 18 mL/min. The solutions from the chiral 15 separation can be concentrated under vacuum (15 psi, 35 'C) to afford the resolved enantiomers. Analytical determination of enantiomeric excess (ee): ChiralPak IA 250 x 4.6 mm ID, 5pim, 0.1 % DEA in 80/20 hexane/EtOH at 1 mL/min at ambient temperature, with UV analysis at 20 230 nm. Enantiomers eluted at 11.35 and 16.51 min, each with > 9 0% enantiomeric excess. Analytical purity: Acquity UPLC BEH C18 100 x 2.1 mm ID, 1.7tm, 0.025 % TFA in a gradient H20:ACN (T/%B, 0/30, 4/80, 6/80, 6.1/30) at 0.4 mL/min at ambient temperature, with UV analysis at 229 nm. Elution at 1.64 min, each with > 95.0% purity. Without being 25 bound by theory, it is believed that mixtures, e.g., racemates corresponding to a compound of Formula (I), (Ia), (Ib), (II) or (III) can be resolved in the individual enantiomers or an enantiomer substantially free of the other enantiomer. Thus, the skilled artisan, in view of the disclosure described herein can isolate or purify enantiomers from racemates or mixtures of enantiomers in view of the disclosure herein utilizing standard organic chemistry 30 techniques for separating enantiomers. Enantiomer 1, the (-) optical stereoisomer of 5-(((trans)-2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine is characterized as WO 2012/013728 PCT/EP2011/062949 130 follows: 1 HNMR (400 MHz, DMSO d6) 6: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H), 0.92 (in, 2H); Mass (M+H): 337.1; HPLC Purity: 96.02 %; Chiral HPLC Purity: 95.18 %; Specific optical rotation [UID27.2 (c=0.5 % in DMSO): - 37.76. 5 Enantiomer 2, the (+) optical stereoisomer of 5-(((trans)-2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine is characterized as follows: 'HNMR (400 MHz, DMSO d6) 6: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H), 0.92 (in, 2H); Mass (M+H): 10 337.1; HPLC Purity: 98.16 %; Chiral HPLC Purity: 98.34 %; Specific optical rotation [ID 26.9 (c=0.5 % in DMSO): + 37.76'. The optical activity determination experiment was performed with a Jasco-P-1030 Polarimeter at a temperature of about 26.9 and 27.2 and a compound concentration (0.5%) 15 and solvent of choice e.g., (DMSO). Example 37: Determination of Kinetic Parameters for Optically Active Compounds of the Invention The kinetic parameters of LSD1 demethylase inhibition were obtained using the peroxidase 20 coupled reaction method. In this assay the demethylase reaction was initiated by simultaneously mixing LSD 1 protein (either 31 nM or 10 nM) (BPS), 31.25 tM H3-K4me2 peptide (Millipore), increasing concentrations of test compound (e.g., an optically active stereoisomer of 5-(((Trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4 oxadiazol-2-amine or an optically active N-substituted aryl- or heteroaryl 25 cyclopropylamine compound) and 50ptM Amplex@ Red and 0,1U/ml horseradish peroxidase (HPR) (Invitrogen) in a buffer containing 50mM sodium phosphate buffer pH=7.4. The final DMSO concentration was 0.7% and constant in all assay wells. The conversion of the Amplex@ Red reagent to resorufin due to generation of H 2 0 2 was 30 continuously monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). A solution of 1 M H202 was used to calibrate the fluorescence signal and the temperature was kept constant at 25'C.
WO 2012/013728 PCT/EP2011/062949 131 Kinetic parameters were obtained following the method described by Szewczuk et al ((2007) Biochemistry, 46, 6892-6902). 5 Briefly, progress curves obtained in the presence of test compound were fit to derive kobs (k) based on the following equation: product =- Gffset The kobs values were then used to derive the kinetic constant by using the following equations (Kitz and Wilson analysis): 10 with Km = 24pM. 15 The determination of the kinetic inhibition constants for MAOs was done following the same protocol as for LSD1 with the following modifications: For MAO-A, the protein was kept at 1,8ng/ul (Sigma M7316) and kynuramine (Sigma) at 64uM was used as substrate. In this case the Kim was 64 uM. 20 For MAO-B, the protein was kept between 1.8 and 3.6ng/ul (Sigma M7441) and kynuramine (Sigma) at 50uM was used as substrate. In this case the Km was 32 uM. For both MAO assays, the final DMSO concentrations were 0.54%. 25 Selegine hydrochloride and rasagiline mesylate were obtained from Sigma-Aldrich and Carbone Scientific Co. Ltd respectively. These studies were used to calculate the values obtained in Table 1. 30 WO 2012/013728 PCT/EP2011/062949 132 Table 1: The Catalytic Efficiency, kinact/K1, Obtained for the Enantiomers of 5-(((Trans)-2 (4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,3,4-oxadiazol-2-amine -1 -1 kinact/Ki (M S) Enantiomer -1 Enantiomer -2 Selegiline Rasagiline (-) optical (+) optical antipode antipode LSDI 15,516 767 Inactive Inactive MAO-A 17 182 <100 62 MAO-B 38,298 34,940 32,500 7,463 The results described herein show that the (-) stereoisomer of 5-(((trans)-2-(4 5 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine is a potent, highly selective inhibitor of LSD1 and MAOB. The selectivity of the (-) stereoisomer of 5 (((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,3,4-oxadiazol-2-amine for LSD1, MAO-A, and MAO-B as judged by the selectivity index kinact/K1 indicates that the compound is highly selective for both LSD1 and MAO-B. In particular, the selectivity 10 index of the (-) stereoisomer of 5-(((trans)-2-(4 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine for MAO-B/MAO A is about 2253 and is thus more advantageous than the corresponding values for Rasagiline and Selegiline which are 120 and < 325, respectively. The selectivity index of the (+) stereoisomer of 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4 15 oxadiazol-2-amine for MAO-B/MAO-A is about 192. Furthermore, other irreversible monoamine oxidase inhibitors like Rasagiline and Selegiline are not active against LSD1 in these assays. Notably, the ratio of kinact/K1 for LSD1/MAO-A was over 100-larger for the ( ) stereoisomer as compared to the (+) stereoisomer of 5-(((trans)-2-(4- WO 2012/013728 PCT/EP2011/062949 133 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine. Thus, the inventors have unexpectedly found that optically active N-substituted aryl- or heteroaryl trans-cyclopropylamine compounds, including the compounds of Formula (I), wherein the substituents on the cyclopropyl moiety are in trans orientation, as well as the compounds of 5 Formula (II) or (III), have unexpected selectivity for inhibiting LSD1 and for inhibiting LSD1 and MAO-B. Example 38: Biological Assays 10 The compounds of the invention can be tested for their ability to inhibit LSD 1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc. In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di methylated H3-K4 peptide (Millipore) was chosen as a substrate. The demethylase activity 15 was estimated, under aerobic conditions, by measuring the release of H 2 0 2 produced during the catalytic process, using the Amplex@ Red peroxide/peroxidase-coupled assay kit (Invitrogen, Carlsbad, CA). Briefly, a fixed amount of LSD 1 was incubated on ice for 15 minutes, in the absence and/or 20 in the presence of various concentrations of inhibitor (e.g., from 0 to 75 pjM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, 12.5 pM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes (or e.g., an 25 hour) at 37'C in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex@ Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and mixed well for 5 minutes (e.g., or alternatively 30 mintues) at room temperature in the dark. A 1 pM H 2 0 2 solution was 30 used as a control of the kit efficiency. The conversion of the Amplex@ Red reagent to resorufin due to the presence of H 2 0 2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 rn) using a microplate reader (Infinite 200, Tecan).
WO 2012/013728 PCT/EP2011/062949 134 Arbitrary units were used to measure level of H 2 0 2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and 5 corrected for background fluorescence in the absence of LSD1. The Ki (IC50) of each inhibitor was estimated at half of the maximum activity. The results presented in Table 2 below show the results of the LSD1 inhibition studies for a number of the Example compounds. Parnate (2-trans phenylcyclopropylamine) was found 10 to have a Ki (IC50) of from about 15 to 35 micromolar depending on the enzyme preparation. The studies show that the compounds of the invention have unexpectedly potent LSD 1 inhibition. Example 39: Biological Assays - Monoamine Oxidase Assays for determining the 15 selectivity of the compounds of the invention for LSD 1 Human recombinant monoamine oxidase proteins MAO-A and MAO-B were purchased from Sigma Aldrich. MAOs catalyze the oxidative deamination of primary, secondary and tertiary amines. In order to monitor MAO enzymatic activities and/or their inhibition rate 20 by inhibitor(s) of interest, a fluorescent-based (inhibitor)-screening assay was set up. 3-(2 Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, Sigma Aldrich), a non fluorescent compound was chosen as a substrate. Kynuramine is a non-specific substrate for both MAOs activities. While undergoing oxidative deamination by MAO activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ), a resulting fluorescent product. 25 The monoamine oxidase activity was estimated by measuring the conversion of kynuramine into 4-hydroxyquinoline. Assays were conducted in 96-well black plates with clear bottom (Coming) in a final volume of 100 ptL. The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performed in triplicate within the same experiment. 30 Briefly, a fixed amount of MAO (0.25 ptg for MAO-A and 0.5 ptg for MAO-B) was incubated on ice for 15 minutes in the reaction buffer, in the absence and/or in the presence WO 2012/013728 PCT/EP2011/062949 135 of various concentrations of inhibitor (e.g., from 0 to 50 pM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 ptM of kynuramine was 5 added to each reaction for MAO-B and MAO-A assay respectively, and the reaction was left for 1 hour at 37'C in the dark. The oxidative deamination of the substrate was stopped by adding 50 ptL (v/v) of NaOH 2N. The conversion of kynuramine to 4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure levels of 10 fluorescence produced in the absence and/or in the presence of inhibitor. The maximum of oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from kynuramine deamination in the absence of inhibitor and corrected for background fluorescence in the absence of MAO enzymes. The Ki (IC50) of 15 each inhibitor was determined at Vmax/2. Example MAO-A MAO-B LSD1 No. (Ki) (Ki) (Ki) 1 I II III 2 I I III 10 I II 11-III 11 I II II 12 I II II 13 I II II 14 I II II 15 I II II-III Table 2: Summary of Data from MAO-A, MAO-B, and LSD1 Inhibition Studies The ranges for the Ki value reported in Table 2 are for MAO-A, MAO-B and LSD1 - I 20 between 1 gM and 40 jiM; II = between 0.1 jiM and 1 piM; III between 0.001 jiM and 0.1 gM. Generally the compounds of the Examples were found to have Ki (IC50) values for MAO-A and MAO-B greater than the LSD1 Ki values, whereas LSD1 Ki values were lower than 0.6 25 gM.
WO 2012/013728 PCT/EP2011/062949 136 Thus the compounds of the invention are unexpectedly potent LSD1 inhibitors and unexpectedly selective for LSD1 as compared to MAO-A and MAO-B, or the compounds are dual inhibitors of LSD1 and MAO-B. 5 Some compounds of the Examples have been tested for antiproliferative/cytotoxic activity and been found to have activity in the micromolar to low micromolar range against cancer cell lines including HCT- 116. 10 Previous reports of LSD1 have found that it is involved in cell proliferation and growth. Some studies have implicated LSD1 as a therapeutic target for cancer. Huang et al. (2007) PNAS 104:8023-8028 found that polyamine inhibitors of LSD1 modestly cause the reexpression of genes aberrantly silenced in cancer cells and particularly colorectal cancer (Huang et al. Clin Cancer Res. (2009) Dec 1;15(23):7217-28. Epub 2009 Nov 24. PMID: 15 19934284). Scoumanne et al. ((2007) J. Biol. Chem. May 25;282(21):15471-5) found that deficiency in LSD1 leads to a partial cell cycle arrest in G2/M and sensitizes cells to growth suppression induced by DNA damage. Kahl et al. ((2006) Cancer Res. 66(23):11341-7.) found that LSD1 expression is correlated with prostate cancer aggressiveness. Metzger et al. reported that LSD1 modulation by siRNA and pargyline regulates androgen receptor 20 (AR) and may have therapeutic potential in cancers where AR plays a role, like prostate, testis, and brain cancers. Lee et al. ((2006) Chem. Biol. 13:563-567) reported that tranylcypromine derepresses Egr-1 gene expression in some cancer lines. A body of evidence is accumulating that Egr-1 is a tumor suppressor gene in many contexts (see e.g., Calogero et al. (2004) Cancer Cell International 4:1 exogenous expression of EGR-1 25 resulted in growth arrest and eventual cell death in primary cancer cell lines; Lucerna et al. (2006) Cancer Research 66, 6708-6713 show that sustained expression of Egr-1 causes antiangiogeneic effects and inhibits tumor growth in some models; Ferraro et al. ((2005) J. Clin. Oncol. Mar 20;23(9):1921-6) reported that Egr-1 is downregulated in lung cancer patients with a higher risk of recurrence and may be more resistant to therapy. Thus, 30 increasing Egr-1 expression via inhibition of LSD1 is a therapeutic approach for some cancers. Recent studies have also implicated LSDI in brain cancer (Schulte et al. (2009) Cancer Res. Mar 1;69(5):2065-71). Other studies have implicated LSD1 in breast cancer (Lims et al. Carcinogenesis. 2009 Dec 30. [Epub ahead of print] PMID: 20042638).
137 Thus, a body of evidence has implicated LSD1 in a number of cancers, which suggests that LSD1 is a therapeutic target for cancer. The instant inventors have discovered a class of LSD1 inhibitors that can be used to treat diseases where LSD 1 is implicated as a therapeutic target like cancer. Accordingly, the phenylcyclopropylamine compounds of the invention can be used to treat such diseases. Recent studies have also implicated LSD 1 in viral infection and reactivation. In particular it was shown that pharmacological inhibitors of LSD1 like parnate and siRNA knock down of LSD1 caused reduced viral infectivity and reduced reactivation after latency (Liang et al. (2009) Nat. Med. 15:1312-1317). Therefore it is believed that the compounds of the invention can be used for treating or preventing viral infection. Furthermore, it is believed that the compounds of the invention can treat or prevent viral reactivation after latency. Thus, without being bound by theory, the inventors have identified a new class of cyclopropanamine derivatives containing LSD1 inhibitors with unexpected potency and selectivity for LSD1 a biologically relevant target in oncology and other diseases and/or LSD1/MAO-B. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
137A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (51)

1. A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof: (B)- (A)N 5 (D) (I) wherein: D (A) is a cyclyl group having n substituents (R3); (B) is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclyl group or the cyclyl moiety comprised in said -(L1)-cyclyl group has n substituents (R2); 5 (LI) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene; (D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein said heteroaryl group or the heteroaryl moiety comprised in said -(L2)-heteroaryl group has one substituent (RI), and further wherein said heteroaryl group is covalently bonded to the 0O remainder of the molecule through a ring carbon atom or the heteroaryl moiety comprised in said -(L2)-heteroaryl group is covalently bonded to the (L2) moiety through a ring carbon atom; (L2) is -0-, -NH-, -N(alkyl)-, alkylene or heteroalkylene; :5 (RI) is a hydrogen bonding group; each (R2) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, 0 sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea; 139 each (R3) is independently selected from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and 5 n is independently 0, 1, 2, 3 or 4.
2. The compound of claim 1 wherein (A) is an aryl group or a heteroaryl group, wherein said aryl group or said heteroaryl group has n substituents (R3). D
3. The compound of claim 1 wherein (A) is phenyl or pyridyl, and further wherein said phenyl or said pyridyl has n substituents (R3).
4. The compound of claim 1 wherein (A) is phenyl, and further wherein said phenyl has n substituents (R3). 5
5. The compound of any one of claims 1 to 4 wherein (A) has 0 substituents (R3).
6. The compound of any one of claims I to 5 wherein (B) is a cyclyl group or an -(Li) cyclyl group, wherein said cyclyl group or the cyclyl moiety comprised in said D (L1)-cyclyl group has n substituents (R2), and wherein said cyclyl group or the cyclyl moiety comprised in said -(L1)-cyclyl group is an aryl group or a heteroaryl group.
7. The compound of any one of claims 1 to 5 wherein (B) is -O-CH 2 -phenyl or phenyl, :5 and further wherein said phenyl or the phenyl moiety comprised in said -O-CH 2 phenyl has n substituents (R2).
8. The compound of any one of claims 1 to 5 wherein (B) is -O-CH 2 -phenyl, and further wherein the phenyl moiety comprised in said -O-CH 2 -phenyl has n 0 substituents (R2).
9. The compound of any one of claims 1 to 8 wherein (B) has 0, 1 or 2 substituents (R2). 140
10. The compound of any one of claims 1 to 9, wherein (D) is a monocyclic heteroaryl group, wherein said heteroaryl group has one substituent (RI), and further wherein said heteroaryl group is covalently bonded to the remainder of the molecule through 5 a ring carbon atom.
11. The compound of any one of claims I to 10 wherein (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl, and further wherein said thiazolyl, said oxadiazolyl, said oxazolyl, said D isoxazolyl, said thiadiazolyl, said triazinyl, said pyridazinyl, said pyrazinyl, said pyridinyl or said pyrimidinyl has one substituent (RI).
12. The compound of any one of claims 1 to 11 wherein (D) is oxadiazolyl, wherein said oxadiazolyl has one substituent (RI). 5
13. The compound of any one of claims 1 to 12 wherein (RI) is -OH, -O(alkyl), -NH 2 , -NH(alkyl), -N(alkyl)(alkyl), amido, -SO-NH 2 , -SO-NH(alkyl), -SO-N(alkyl)(alkyl), -S(O) 2 NH2, -S(O) 2 NH(alkyl), -S(O) 2 N(alkyl)(alkyl), -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl)(alkyl), -alkylene-C(=O)NH 2 , -alkylene-C(=O)NH(alkyl), D -alkylene-C(=O)N(alkyl)(alkyl), -NHC(=O)-alkyl, -N(alkyl)-C(=O)-alkyl, -alkylene-NH 2 , -alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl).
14. The compound of any one of claims 1 to 13 wherein (RI) is -OH, -NH 2 , amido, -S(O) 2 NH 2 , -C(=O)NH 2 , -CH 2 -C(=O)NH 2 , -NHC(=O)CH 3 , -NHCH 3 , -N(CH 3 ) 2 or :5 -CH 2 -NH 2 .
15. The compound of any one of claims I to 14 wherein (RI) is -NH 2 .
16. The compound of any one of claims 1 to 15 wherein (R2) is independently selected 0 from hydroxyl, halo or haloalkyl.
17. The compound of any one of claims I to 16 wherein (R2) is halo. 141
18. The compound of any one of claims I to 17 wherein (R2) is -F.
19. The compound of any one of claims 1 to 18 wherein the substituents on the cyclopropyl moiety are in trans-configuration. 5
20. The compound of claim 1 wherein said compound is selected from: 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 9 yl)cyclopropylamino)methyl)pyrimidin-2-amine; 5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropylamino)methyl)thiazol-2-amine; 3 -(5 -((trans)-2-((2-aminopyrimidin-5 -yl)methylamino)cyclopropyl)pyridin-2 yl)phenol; 5 3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol; 4'-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 4'-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol; 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3 amine; D 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2 amine; 5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 5 oxadiazol-2-amine; 5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 0 5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4 oxadiazol-2-amine; 142 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4 oxadiazol-2-amine; N-(5 -((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol 2-yl)acetamide; 5 4'-((trans)-2-(((5-amino- 1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1' biphenyl]-3-ol; 5 -((((trans)-2-(6-(3 -(trifluoromethyl)phenyl)pyridin-3 yl)cyclopropyl)amino)methyl)- 1,3,4-oxadiazol-2-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)- 1,3,4-thiadiazol-2 9 amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol -5-amine; 4-((((trans)-2-(3'-(trifluoromethyl)-[1,1 '-biphenyl]-4 yl)cyclopropyl)amino)methyl)thiazol-2-amine; 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine; 5 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3 amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5 amine; D 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3 amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine; 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine; :5 2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5 -amine; 6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3 amine; 3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6 amine; 0 or a pharmaceutically acceptable salt or solvate thereof.
21. The compound of claim 1 wherein said compound is 143 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)- 1,3,4-oxadiazol-2 amine or a pharmaceutically acceptable salt or solvate thereof.
22. The compound of claim 1 wherein said compound is 5-((((trans)-2-(4-((4 5 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof.
23. The compound of claim 1 wherein said compound is 5-((((trans)-2-(4-((3 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a D pharmaceutically acceptable salt or solvate thereof.
24. The compound of claim 1 wherein said compound is 5-((((trans)-2-(4-((3,5 difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof. 5
25. The compound of claim 1 wherein said compound is 5-((((trans)-2-(4-((2 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof D
26. The compound of claim 1 wherein said compound is 5-((((trans)-2-(6-(3 (trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 amine; or a pharmaceutically acceptable salt or solvate thereof.
27. The compound of claim 1 wherein said compound is 3-((((trans)-2-(4 :5 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine; or a pharmaceutically acceptable salt or solvate.
28. The compound of any of claims 19 to 27 wherein said compound is an optically active stereoisomer. 0
29. The compound of any of claims 19 to 28 wherein said compound is the (-) stereoisomer. 144
30. The compound of any of claims 19 to 28 wherein said compound is the (+) stereoisomer.
31. The compound of claim 1 wherein said compound is (-) 5-(((trans)-2-(4 5 (benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.
32. The compound of claim 1 wherein said compound is (-) 5-((((trans)-2-(4-((3 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a D pharmaceutically acceptable salt or solvate thereof.
33. The compound of claim 1 wherein said compound is (-) 5-((((trans)-2-(4-((2 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof. 5
34. The compound of claim 1 wherein said compound is (-) 5-((((trans)-2-(4-((4 fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof. D
35. The compound of claim 1 wherein said compound is (-) 5-((((trans)-2-(4-((3,5 difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof
36. The compound of claim 1 wherein said compound is (-) 5-((((trans)-2-(6-(3 5 (trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2 amine; or a pharmaceutically acceptable salt or solvate thereof
37. The compound of claim 1 wherein said compound is (-) 3-((((trans)-2-(4 (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine; or a 0 pharmaceutically acceptable salt or solvate thereof
38. A pharmaceutical composition comprising the compound of any one of claims 1 to 37 and a pharmaceutically acceptable carrier. 145
39. Use of a compound of any one of claims 1 to 37 in the manufacture of a medicament. 5
40. Use of the compound of any one of claims 1 to 37 or the pharmaceutical composition of claim 38 in the manufacture of a medicament for treating or preventing a neurological disease or disorder.
41. A method of treating or preventing a neurological disease or disorder, the method D comprising administering, to a subject in need of such treatment or prevention, the compound of any one of claims 1 to 37 or the pharmaceutical composition of claim 38.
42. The use of claim 40 or the method of claim 41 wherein said neurological disease or 5 disorder is selected from Alzheimer's disease, Huntington disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.
43. Use of the compound of any one of claims 1 to 37 or the pharmaceutical composition D of claim 38 the manufacture of a medicament for treating or preventing cancer.
44. A method of treating or preventing cancer, the method comprising administering, to a subject in need of such treatment or prevention, the compound of any one of claims I to 37 or the pharmaceutical composition of claim 38. :5
45. The use of claim 43 or the method of claim 44 wherein said cancer is selected from prostate cancer, breast cancer, lung cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia, lymphoma, or myeloma. 0
46. Use of the compound of any one of claims 1 to 37 or the pharmaceutical composition of claim 38 in the manufacture of a medicament for treating or preventing a viral infection or for treating or preventing viral reactivation after latency. 146
47. A method of treating or preventing a viral infection or viral reactivation after latency, the method comprising administering, to a subject in need of such treatment or prevention, the compound of any one of claims 1 to 48 or the pharmaceutical composition of claim 38. 5
48. The use of claim 46 or the method of claim 47 wherein said viral infection is a herpesvirus infection, or said viral infection is caused by and/or associated with HIV; or said virus that is reactivating is a herpesvirus. D
49. A method of inhibiting histone-3 lysine-4 demethylation or histone-3 lysine-9 demethylation, the method comprising administering, to a subject in need thereof, the compound of any one of claims 1 to 38 or the pharmaceutical composition of claim 38. 5
50. The method of any one of claims 41, 42, 44, 45, 47, 49 or 49, wherein said subject is a human.
51. The compound of any one of claim 1 to 37, or the composition of claim 38, or the use of any one of claims 39, 40, 42, 43, 45, 46 or 48, or the method of any one of D claims 41, 42, 44, 47, 49 or 50, substantially as hereinbefore described with reference to the figures and/or examples.
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Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2361242B1 (en) 2008-10-17 2018-08-01 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2010084160A1 (en) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
EP2486002B1 (en) 2009-10-09 2019-03-27 Oryzon Genomics, S.A. Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use
WO2011106106A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
WO2011106574A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
CA2796726C (en) 2010-04-19 2021-02-16 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
RS57331B1 (en) 2010-07-29 2018-08-31 Oryzon Genomics Sa Arylcyclopropylamine based demethylase inhibitors of lsd1 and their medical use
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
WO2012045883A1 (en) * 2010-10-08 2012-04-12 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
US20140163041A1 (en) 2011-02-08 2014-06-12 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders
EP2712315B1 (en) 2011-02-08 2021-11-24 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
MX347913B (en) 2011-03-25 2017-05-17 Glaxosmithkline Intellectual Property (No 2) Ltd Cyclopropylamines as lsd1 inhibitors.
EP2741741A2 (en) 2011-05-19 2014-06-18 Oryzon Genomics, S.A. Lysine demethylase inhibitors for inflammatory diseases or conditions
WO2012156537A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for thrombosis and cardiovascular diseases
CN104203914B (en) 2011-10-20 2017-07-11 奥瑞泽恩基因组学股份有限公司 As (miscellaneous) aryl rings propanamine compounds of LSD1 inhibitor
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
CN105051005B (en) * 2012-10-12 2017-06-13 武田药品工业株式会社 Cyclopropylamine compound and application thereof
CN102863341B (en) * 2012-10-22 2014-05-07 南通大学 Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative
EP2740474A1 (en) 2012-12-05 2014-06-11 Instituto Europeo di Oncologia S.r.l. Cyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a
EP3003301B1 (en) * 2013-05-30 2021-02-24 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas Novel suicidal lsd1 inhibitors targeting sox2-expressing cancer cells
AU2014306149B2 (en) 2013-08-06 2019-09-19 Imago Biosciences Inc. KDM1A inhibitors for the treatment of disease
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
HUE045725T2 (en) 2014-02-13 2020-01-28 Incyte Corp Cyclopropylamines as lsd1 inhibitors
AU2015217073B2 (en) * 2014-02-13 2019-08-22 Incyte Holdings Corporation Cyclopropylamines as LSD1 inhibitors
EP3392244A1 (en) 2014-02-13 2018-10-24 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
UY36071A (en) 2014-04-11 2015-11-30 Takeda Pharmaceutical CYCLOPROPANAMINE COMPOUND AND ITS USES
WO2016007736A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Imidazopyrazines as lsd1 inhibitors
TWI687419B (en) 2014-07-10 2020-03-11 美商英塞特公司 Imidazopyridines and imidazopyrazines as LSD1 inhibitors
WO2016007722A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines and triazolopyrazines as lsd1 inhibitors
WO2016007727A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines and triazolopyrazines as lsd1 inhibitors
AU2015309686B2 (en) 2014-08-25 2020-05-14 Epiaxis Therapeutics Pty Ltd Compositions for modulating cancer stem cells and uses therefor
EA039196B1 (en) * 2014-10-08 2021-12-16 Инсайт Корпорейшн Cyclopropylamines as lsd1 inhibitors
WO2016123387A1 (en) * 2015-01-30 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
KR102626978B1 (en) 2015-02-12 2024-01-18 이마고 바이오사이언시즈 인코포레이티드 Kdm1a inhibitors for the treatment of disease
TWI714567B (en) 2015-04-03 2021-01-01 美商英塞特公司 Heterocyclic compounds as lsd1 inhibitors
EP3090998A1 (en) 2015-05-06 2016-11-09 F. Hoffmann-La Roche AG Solid forms
EP3307909A1 (en) 2015-06-12 2018-04-18 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
WO2017013061A1 (en) 2015-07-17 2017-01-26 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
MY189367A (en) 2015-08-12 2022-02-08 Incyte Corp Salts of an lsd1 inhibitor
US10059668B2 (en) 2015-11-05 2018-08-28 Mirati Therapeutics, Inc. LSD1 inhibitors
PT3381896T (en) 2015-11-27 2023-03-06 Taiho Pharmaceutical Co Ltd Novel biphenyl compound or salt thereof
WO2017109061A1 (en) * 2015-12-23 2017-06-29 Ieo - Istituto Europeo Di Oncologia S.R.L. Spirocyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a
KR20180117602A (en) 2015-12-29 2018-10-29 미라티 테라퓨틱스, 인크. LSD1 inhibitor
CN107176927B (en) * 2016-03-12 2020-02-18 福建金乐医药科技有限公司 Histone demethylase LSD1 inhibitors
MX2018011100A (en) 2016-03-15 2019-01-10 Oryzon Genomics Sa Combinations of lsd1 inhibitors for the treatment of hematological malignancies.
EA201892075A1 (en) 2016-03-15 2019-04-30 Оризон Дженомикс, С.А. COMBINATION OF LSD1 INHIBITORS FOR USE FOR THE TREATMENT OF SOLID TUMORS
CN107200706A (en) 2016-03-16 2017-09-26 中国科学院上海药物研究所 Cyclopropylamine class compound of one class fluorine substitution and preparation method thereof, pharmaceutical composition and purposes
EP3430015A1 (en) 2016-03-16 2019-01-23 Oryzon Genomics, S.A. Methods to determine kdm1a target engagement and chemoprobes useful therefor
EP3445339B1 (en) 2016-04-22 2023-08-23 Incyte Corporation Formulations of an lsd1 inhibitor
SI3307267T1 (en) 2016-06-10 2019-08-30 Oryzon Genomics, S.A. Multiple sclerosis treatment
CN111194306B (en) 2016-08-16 2023-05-16 伊美格生物科学公司 Methods and processes for preparing KDM1A inhibitors
WO2018083189A1 (en) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
EP3541372A1 (en) * 2016-11-17 2019-09-25 Cytoo Lsd1 inhibitors as skeletal muscle hypertrophy inducers
WO2018106984A1 (en) 2016-12-09 2018-06-14 Constellation Pharmaceuticals, Inc. Markers for personalized cancer treatment with lsd1 inhibitors
CA3056527A1 (en) 2017-01-24 2018-08-02 Medshine Discovery Inc. Lsd1 inhibitor and preparation method and application thereof
JP6843979B2 (en) 2017-05-26 2021-03-17 大鵬薬品工業株式会社 New biphenyl compound or salt thereof
DK3632443T3 (en) 2017-05-26 2023-09-11 Taiho Pharmaceutical Co Ltd POTENTIATOR OF ANTI-TUMOR EFFECT USING A BIPHENYL COMPOUND
MA50518A (en) * 2017-05-31 2020-09-09 Taiho Pharmaceutical Co Ltd METHOD OF PREDICTING THE THERAPEUTIC EFFECT OF AN LSD1 INHIBITOR BASED ON INSM1 EXPRESSION
JP2020152641A (en) * 2017-07-07 2020-09-24 国立研究開発法人理化学研究所 Novel compound having lysine-specific demethylating enzyme 1 inhibitory activity, method for producing the same, and use of the same
CN110996949A (en) * 2017-08-03 2020-04-10 奥瑞泽恩基因组学股份有限公司 Methods for treating behavioral changes
WO2019068326A1 (en) 2017-10-05 2019-04-11 Université D'aix-Marseille Lsd1 inhibitors for the treatment and prevention of cardiomyopathies
KR20210008064A (en) 2018-05-11 2021-01-20 이마고 바이오사이언시즈 인코포레이티드 KDM1A inhibitors for the treatment of diseases
WO2020015745A1 (en) * 2018-07-20 2020-01-23 南京明德新药研发有限公司 Salt of lsd1 inhibitor and a polymorph thereof
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
CN112672994B (en) * 2018-09-13 2022-09-13 南昌弘益药业有限公司 Heterospiro compounds serving as LSD1 inhibitor and application thereof
CN113631164A (en) 2019-03-20 2021-11-09 奥莱松基因组股份有限公司 Methods of treating attention deficit hyperactivity disorder using KDM1A inhibitors such as the compound varespita
CA3130638A1 (en) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Methods of treating borderline personality disorder
JP2022546908A (en) 2019-07-05 2022-11-10 オリゾン・ゲノミクス・ソシエダッド・アノニマ Biomarkers and methods for personalized treatment of small cell lung cancer using KDM1A inhibitors
JP2022546134A (en) 2019-09-03 2022-11-02 オリソン ヘノミクス，ソシエダ アノニマ Bafidemstat for use in the treatment of autism spectrum disorders
CN115551501B (en) * 2020-05-12 2024-03-22 石药集团中奇制药技术（石家庄）有限公司 Application of LSD1 inhibitor
EP3964204A1 (en) 2020-09-08 2022-03-09 Université d'Aix-Marseille Lsd1 inhibitors for use in the treatment and prevention of fibrosis of tissues
EP4319732A1 (en) 2021-04-08 2024-02-14 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
CN113582906B (en) * 2021-08-24 2023-05-16 郑州大学 Difluoro benzphetamine compound and preparation method and application thereof
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043721A1 (en) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use

Family Cites Families (130)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106578A (en) 1960-09-16 1963-10-08 Smith Kline French Lab Nu-phenethyl-2-phenylcyclopropylamine derivatives
US3365458A (en) 1964-06-23 1968-01-23 Aldrich Chem Co Inc N-aryl-n'-cyclopropyl-ethylene diamine derivatives
US3532749A (en) 1965-05-11 1970-10-06 Aldrich Chem Co Inc N'-propargyl-n**2-cyclopropyl-ethylenediamines and the salts thereof
US3532712A (en) 1967-09-29 1970-10-06 Aldrich Chem Co Inc N'-cyclopropyl ethylenediamine derivatives
US3471522A (en) 1967-09-29 1969-10-07 Aldrich Chem Co Inc N-cyclopropyl-n'-furfuryl-n'-methyl ethylene diamines
US3654306A (en) 1970-01-26 1972-04-04 Robins Co Inc A H 5-azaspiro(2.4)heptane-4 6-diones
US3758684A (en) 1971-09-07 1973-09-11 Burroughs Wellcome Co Treating dna virus infections with amino purine derivatives
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
US4409243A (en) 1981-11-09 1983-10-11 Julian Lieb Treatment of auto-immune and inflammatory diseases
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
GB9311282D0 (en) 1993-06-01 1993-07-21 Rhone Poulenc Rorer Ltd New compositions of matter
EP1275635A1 (en) 1994-10-21 2003-01-15 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US5652258A (en) 1995-05-30 1997-07-29 Gliatech, Inc. 2-(4-imidazoyl) cyclopropyl derivatives
US20040132820A1 (en) 1996-02-15 2004-07-08 Jean Gosselin Agents with leukotriene B4-like antiviral (DNA) and anti-neoplastic activities
GB9615730D0 (en) 1996-07-26 1996-09-04 Medical Res Council Anti-viral agent 1
US5961987A (en) 1996-10-31 1999-10-05 University Of Iowa Research Foundation Ocular protein stimulants
DE19647615A1 (en) 1996-11-18 1998-05-20 Bayer Ag Process for the preparation of cyclopropylamines
AR017014A1 (en) 1997-07-22 2001-08-22 Astrazeneca Ab TRIAZOL COMPOUNDS [4,5-D] PYRIMIDINE, PHARMACEUTICAL COMPOSITIONS, USE OF THE SAME TO PREPARE MEDICATIONS AND PROCESSES FOR THE PREPARATION OF SUCH COMPOUNDS
SE9702772D0 (en) 1997-07-22 1997-07-22 Astra Pharma Prod Novel compounds
AU1631699A (en) 1997-12-18 1999-07-05 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
US6809120B1 (en) 1998-01-13 2004-10-26 University Of Saskatchewan Technologies Inc. Composition containing propargylamine for enhancing cancer therapy
SK285779B6 (en) * 1998-01-16 2007-08-02 Medivir Ab Antiviral compounds
PT1071752E (en) 1998-04-21 2003-11-28 Micromet Ag SPECIFIC POLYMPEPTIDES FOR CD19XCD3 AND ITS USES
SE9802206D0 (en) 1998-06-22 1998-06-22 Astra Pharma Inc Novel compounds
GB2344337A (en) 1998-12-02 2000-06-07 Fcp Carton having a rim
TWI229674B (en) 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
CN100384847C (en) 2000-05-26 2008-04-30 先灵公司 Adenosine a2a receptor antagonists
TWI290549B (en) * 2000-06-02 2007-12-01 Astrazeneca Ab Process for the preparation of cyclopropyl carboxylic acid ester and derivatives
JP2001354563A (en) 2000-06-09 2001-12-25 Sankyo Co Ltd Medicine comprising substituted benzylamines
US8519005B2 (en) 2000-07-27 2013-08-27 Thomas N. Thomas Compositions and methods to prevent toxicity of antiinflammatory agents and enhance their efficacy
EP1193268A1 (en) 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases
BR0116411A (en) 2000-12-21 2003-11-11 Vertex Pharma Pyrazole compounds useful as protein kinase inhibitors
CA2442525A1 (en) 2001-03-29 2002-10-10 Mendi Higgins Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
RU2332415C2 (en) 2001-04-27 2008-08-27 Вертекс Фармасьютикалз Инкорпорейтед Pyrazole derivatives, useful as inhibitors of protein kinase
DE10123163A1 (en) 2001-05-09 2003-01-16 Gruenenthal Gmbh Substituted cyclohexane-1,4-diamine derivatives
US20030008844A1 (en) 2001-05-17 2003-01-09 Keryx Biopharmaceuticals, Inc. Use of sulodexide for the treatment of inflammatory bowel disease
WO2003087064A1 (en) 2002-04-18 2003-10-23 Ucb, S.A. Chemical compounds with dual activity, processes for their preparation and pharmaceutical compositions
CA2484209C (en) 2002-05-03 2013-06-11 Exelixis, Inc. Protein kinase modulators and methods of use
US7704995B2 (en) 2002-05-03 2010-04-27 Exelixis, Inc. Protein kinase modulators and methods of use
EP1505966A4 (en) 2002-05-10 2006-08-30 Bristol Myers Squibb Co 1,1-disubstituted cycloalkyl derivatives as factor xa inhibitors
US7456222B2 (en) 2002-05-17 2008-11-25 Sequella, Inc. Anti tubercular drug: compositions and methods
US20040033986A1 (en) 2002-05-17 2004-02-19 Protopopova Marina Nikolaevna Anti tubercular drug: compositions and methods
US6951961B2 (en) 2002-05-17 2005-10-04 Marina Nikolaevna Protopopova Methods of use and compositions for the diagnosis and treatment of infectious disease
ATE503764T1 (en) 2002-05-20 2011-04-15 Bristol Myers Squibb Co HEPATITIS C VIRUS INHIBITORS
US7611704B2 (en) 2002-07-15 2009-11-03 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections using antibodies and immunoconjugates to aminophospholipids
SE0202539D0 (en) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
ATE384724T1 (en) 2002-12-13 2008-02-15 Smithkline Beecham Corp CYCLOPROPYL COMPOUNDS AS CCR5 ANTAGONISTS
CN102267924A (en) 2003-01-08 2011-12-07 诺华疫苗和诊断公司 Antibacterial agents
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
GB0303439D0 (en) 2003-02-14 2003-03-19 Pfizer Ltd Antiparasitic terpene alkaloids
US7186832B2 (en) 2003-02-20 2007-03-06 Sugen Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
US7135575B2 (en) 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
AU2004233835B2 (en) 2003-04-24 2010-02-25 Merck Sharp & Dohme Corp. Inhibitors of Akt activity
DE602004011348T2 (en) 2003-07-03 2009-01-08 Eli Lilly And Co., Indianapolis INDANDERIVATES AS MUSCARIN RECEPTOR AGONISTS
JP4895811B2 (en) 2003-09-11 2012-03-14 ケミア，インコーポレイテッド Cytokine inhibitor
AU2004271741A1 (en) 2003-09-12 2005-03-24 Laboratoires Serono Sa Sulfonamide derivatives for the treatment of diabetes
CN1897950A (en) 2003-10-14 2007-01-17 惠氏公司 Fused-aryl and heteroaryl derivatives and methods of their use
CN1871008A (en) 2003-10-21 2006-11-29 默克公司 Triazolo-pyridazine compounds and derivatives thereof useful in the treatment of neuropathic pain
US7026339B2 (en) * 2003-11-07 2006-04-11 Fan Yang Inhibitors of HCV NS5B polymerase
CA2551944A1 (en) 2003-12-15 2005-06-30 Almirall Prodesfarma Ag 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists
CN1901971A (en) 2003-12-15 2007-01-24 日本烟草产业株式会社 Cyclopropane compounds and pharmaceutical use thereof
CA2549598A1 (en) 2003-12-15 2005-06-30 Japan Tobacco Inc. N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof
US7399825B2 (en) 2003-12-24 2008-07-15 Lipps Binie V Synthetic peptide, inhibitor to DNA viruses
WO2005103003A2 (en) 2004-04-26 2005-11-03 Pfizer Inc. Pyrrolopyridine derivatives and their use as hiv-integrase inhibitors
US20090275099A1 (en) 2004-04-27 2009-11-05 Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function
CN1946678A (en) * 2004-06-28 2007-04-11 特瓦药物精化学品股份有限公司 Isolated atomoxetine impurity, processes for the preparation of atomoxetine impurities and their use as reference standards
DE102004057594A1 (en) 2004-11-29 2006-06-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Substitute pteridine for the treatment of inflammatory diseases
US7741086B2 (en) 2004-12-16 2010-06-22 President And Fellows Of Harvard College Histone demethylation mediated by the nuclear amine oxidase homolog LSD1
DE602005022826D1 (en) 2005-02-18 2010-09-23 Universitaetsklinikum Freiburg Control of androgen receptor-dependent gene expression by inhibition of amine oxidase activity of lysine-specific demethylase (LSD1)
US20060275366A1 (en) 2005-06-02 2006-12-07 Schering Corporation Controlled-release formulation
WO2007002220A2 (en) 2005-06-21 2007-01-04 Bristol-Myers Squibb Company Aminoacetamide acyl guanidines as beta-secretase inhibitors
EP1741708A1 (en) 2005-06-28 2007-01-10 Sanofi-Aventis Deutschland GmbH Heteroaryl-substituted amides comprising an unsaturated or cyclic linker group, and their use as pharmaceuticals
EP2305695A3 (en) 2005-07-25 2011-07-27 Intermune, Inc. Macrocyclic inhibitors of Hepatitis C virus replication
AU2006279943B2 (en) 2005-08-10 2012-02-16 The Johns Hopkins University Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors
US20090203750A1 (en) 2005-08-24 2009-08-13 Alan Kozikowski 5-HT2C Receptor Agonists as Anorectic Agents
GB0517740D0 (en) 2005-08-31 2005-10-12 Novartis Ag Organic compounds
TW200745067A (en) 2006-03-14 2007-12-16 Astrazeneca Ab Novel compounds
ATE449068T1 (en) 2006-05-18 2009-12-15 Syngenta Participations Ag NEW MICROBIOCIDES
US8198301B2 (en) 2006-07-05 2012-06-12 Hesheng Zhang Quinazoline and quinoline derivatives as irreversibe protein tyrosine kinase inhibitors
JP5872755B2 (en) 2006-07-20 2016-03-01 バイカル インコーポレイテッド Compositions and methods for anti-HSV-2 vaccination
WO2008033466A2 (en) 2006-09-14 2008-03-20 Combinatorx (Singapore) Pre. Ltd. Compositions and methods for treatment of viral diseases
US20110092601A1 (en) 2007-04-13 2011-04-21 The Johns Hopkins University Lysine-specific demethylase inhibitors
US7906513B2 (en) 2007-04-26 2011-03-15 Enanta Pharmaceuticals, Inc. Hydrazide-containing hepatitis C serine protease inhibitors
JP5140154B2 (en) 2007-06-27 2013-02-06 アストラゼネカ・アクチエボラーグ Pyrazinone derivatives and their use in the treatment of pulmonary diseases
JP2010535773A (en) 2007-08-10 2010-11-25 グラクソスミスクライン エルエルシー Nitrogen-containing bicyclic chemicals for treating viral infections
ATE519746T1 (en) 2007-09-17 2011-08-15 Abbott Lab ANTIINFECTIOUS PYRIMIDINES AND USES THEREOF
US20100016262A1 (en) 2007-10-18 2010-01-21 Yale University Compositions and methods for reducing hepatotoxicity associated with drug administration and treating non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and associated cirrhosis
US8299123B2 (en) 2007-10-19 2012-10-30 Boehringer Ingelheim International Gmbh CCR10 antagonists
US8481696B2 (en) 2007-12-26 2013-07-09 Shionogi & Co., Ltd. Glycosylated glycopeptide antibiotic derivatives
WO2009109991A2 (en) 2008-01-23 2009-09-11 Sun Pharma Advanced Research Company Ltd., Novel hydrazide containing tyrosine kinase inhibitors
BRPI0906625A2 (en) 2008-01-28 2015-07-14 Janssen Pharmaceutica Nv Thio-2-amino-quinoline-6-substituted derivatives useful as beta-secretase (bace) inhibitors
WO2009117515A2 (en) 2008-03-19 2009-09-24 Aurimmed Pharma, Inc. Novel compounds advantageous in the treatment of central nervous system diseases and disorders
CN102046595B (en) 2008-03-27 2014-03-05 格吕伦塔尔有限公司 Substituted 4-aminocyclohexane derivatives
WO2009145856A1 (en) 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors
EP2303889A1 (en) 2008-06-18 2011-04-06 F. Hoffmann-La Roche AG Halo-substituted pyrimidodiazepines as plkl inhibitors
EP2317992A2 (en) 2008-07-24 2011-05-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preventing or treating viral infection using an inhibitor of the lsd1 protein, a mao inhibitor or an inhibitor of lsd1 and a mao inhibitor
JP5431476B2 (en) 2008-08-01 2014-03-05 アメリカ合衆国 A3 adenosine receptor antagonist and A3 adenosine receptor partial agonist
US8048887B2 (en) 2008-09-11 2011-11-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2010084160A1 (en) * 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
US8299100B2 (en) 2009-01-23 2012-10-30 Northwestern University Potent and selective neuronal nitric oxide synthase inhibitors with improved membrane permeability
KR101411889B1 (en) 2009-02-27 2014-06-27 이난타 파마슈티칼스, 인코포레이티드 Hepatitis c virus inhibitors
MA33358B1 (en) 2009-05-15 2012-06-01 Novartis Ag Arylperidine as aldosterone synthase inhibitors
US8389580B2 (en) * 2009-06-02 2013-03-05 Duke University Arylcyclopropylamines and methods of use
EP2258865A1 (en) 2009-06-05 2010-12-08 Universitätsklinikum Freiburg Lysine-specific demethylase 1 (LSD1) is a biomarker for breast cancer
WO2010143582A1 (en) 2009-06-11 2010-12-16 公立大学法人名古屋市立大学 Phenylcyclopropylamine derivatives and lsd1 inhibitors
WO2011022489A2 (en) 2009-08-18 2011-02-24 The Johns Hopkins University (bis) urea and (bis) thiourea compounds as epigenic modulators of lysine-specific demethylase 1 and methods of treating disorders
EP2475254A4 (en) 2009-09-11 2013-05-22 Enanta Pharm Inc Hepatitis c virus inhibitors
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
EP2486002B1 (en) 2009-10-09 2019-03-27 Oryzon Genomics, S.A. Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use
WO2011057262A2 (en) 2009-11-09 2011-05-12 Evolva Inc. Treatment of infections with tp receptor antagonists
WO2011106574A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
WO2011106106A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
US20130197088A1 (en) 2010-03-12 2013-08-01 Robert A. Casero, JR. Compositions and Methods for Combinations of Oligoamines with 2-Difluoromethylornithine (DFMO)
CA2796726C (en) 2010-04-19 2021-02-16 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2011132083A2 (en) 2010-04-20 2011-10-27 Actavis Group Ptc Ehf Novel process for preparing phenylcyclopropylamine derivatives using novel intermediates
PL2560949T3 (en) 2010-04-20 2017-01-31 Università Degli Studi Di Roma "La Sapienza" Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2
AU2011273101A1 (en) 2010-06-30 2013-01-17 Actavis Group Ptc Ehf Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor
RS57331B1 (en) * 2010-07-29 2018-08-31 Oryzon Genomics Sa Arylcyclopropylamine based demethylase inhibitors of lsd1 and their medical use
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
WO2012034116A2 (en) 2010-09-10 2012-03-15 The Johns Hopkins University Small molecules as epigenetic modulators of lysine-specific demethylase 1 and methods of treating disorders
US20130303545A1 (en) 2010-09-30 2013-11-14 Tamara Maes Cyclopropylamine derivatives useful as lsd1 inhibitors
WO2012045883A1 (en) 2010-10-08 2012-04-12 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
EP2712315B1 (en) 2011-02-08 2021-11-24 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
US20140163041A1 (en) 2011-02-08 2014-06-12 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders
MX347913B (en) 2011-03-25 2017-05-17 Glaxosmithkline Intellectual Property (No 2) Ltd Cyclopropylamines as lsd1 inhibitors.
WO2012156537A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for thrombosis and cardiovascular diseases
EP2741741A2 (en) 2011-05-19 2014-06-18 Oryzon Genomics, S.A. Lysine demethylase inhibitors for inflammatory diseases or conditions
CN104203914B (en) 2011-10-20 2017-07-11 奥瑞泽恩基因组学股份有限公司 As (miscellaneous) aryl rings propanamine compounds of LSD1 inhibitor
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043721A1 (en) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use

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